Triple Negative Breast Cancer Abstracts

April 2013

www.DenverNaturopathic.com

Jacob Schor ND, FABNO

Possible format draft 2

 

 

Triple Negative Breast Cancer Abstracts

 

 

 

 

Adjunctive Therapies to consider:

 

Blueberries

Flax seed and flax seed oil

Berbamine/berberine

Metformin

Breast Defend ™

 

 

  • Blueberries:
  • August 2011 “Whole Blueberry Powder Modulates the Growth and Metastasis of MDA-MB-231 Triple Negative Breast Tumors in Nude Mice.”
  • May 2010 “Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway.”
  • Berbamine:

 

  • October 2009 “Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action”
  • against drug resistance:  “A novel calmodulin antagonist O-(4-ethoxyl-butyl)-berbamine overcomes multidrug resistance in drug-resistant MCF-7/ADR breast carcinoma cells.”
  • Berberine:
    • against highly metastatic BC cells: “Berberine, an isoquinoline alkaloid, inhibits the metastatic potential of breast cancer cells via Akt pathway modulation.”

 

 

  • Flax seed
 
              • September 2005:  “The inhibitory effect of flaxseed on the growth and metastasis of estrogen receptor negative human breast cancer xenograftsis attributed to both its lignan and oil components.”
              • March 2010 “Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF-7 tumor growth through estrogen receptor- and growth factor-signaling pathways.” ‘All treatments reduced the growth of TAM-treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM-treated tumors but FO was more effective’
        • Metformin:
           
              • Apr 2013:  metformin derivatives have stronger effect:
              • Feb 2013  MoA “Metformin induces a senescence-associated gene signature in breast cancer cells.”
              • March 2012: Good BUT Non Significant improvements: MD Anderson Study “Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer.” “At a median follow-up of 62 months, there were no significant differences with regard to 5-year DMFS (P = .23), RFS (P = .38), and OS (P = .58) between the 3 groups. Compared with the metformin group, patients who did not receive metformin (hazard ratio [HR], 1.63; 95% confidence interval [95% CI], 0.87-3.06 [P = .13]) and nondiabetic patients (HR, 1.62; 95% CI, 0.97-2.71 [P = .06]) tended to have a higher risk of distant metastases.”

         

         

              • March 2012: “Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer.”
              • Jan 2012: “Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers.”
              • Jan 2011: “The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells.”
              • September 2010: ‘metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events.’ “Dietary energy availability affects primary and metastatic breast cancer andmetformin efficacy.”
              • 2009: “Expanding the arsenal: metformin for the treatment of triple-negative breast cancer?”
              • http://www.landesbioscience.com/journals/cc/CCNewsViewsCC8-17.pdf
              • Jan 2012: “Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers.”
              • Jan 2011: “The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells.”

         

        • Breast Defend™

         

              • July 2012: “BreastDefend™ prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer.”
              • contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin),

         

        • Vitamin D

         

              • “Vitamin D intake may be effective in the management of triple-negative breast cancer.”
              • Sept 2012: more common in African American women….
              • May respond to active vitamin D.
              • Women more likely to be D deficient than other BC types.
            • “Vitamin D deficiency is correlated with poor outcomes in patients with luminal-type breast cancer.”

              • “The 25-OHD concentration was inversely associated with prognosis of patients with cancer of the luminal A (P = 0.012) and luminal B subtypes (P =0.023), but not with the prognosis of patients with Her2/neu-enriched (P = 0.245) or triple-negative (P = 0.879)cancer subtypes. This association remained valid after adjustment for age, tumor size, nodal status, and estrogen receptor status (hazards ratio = 3.97; 95% confidence interval = 1.77-9.61).”

         

         

        • Curcumin

         

         

         

         

         

         

            •  Caffeic acid phenethyl ester (CAPE),

              • derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer.”CAPE:  from Honey Bee Propolis

                • free text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144783/pdf/nihms291156.pdf
              • Aug 2012: “Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells.”
            • Free text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388256/pdf/10637_2011_Article_9667.pdf

         

        • Aspirin:
          • “may prevent metastasis in patients with triple-negative breast cancer.”
          • reduces recurrence in regular BC: http://naturalmedicinejournal.com/article_content.asp?article=271

         

         

        • Oddities:
        • Hydrogen sulfide releasing aspirin
          • no idea if this is sold retail yet: NOSH-aspirin From Wikipedia, the free encyclopedia: NOSH-Aspirin is a category of new hybrids of aspirin, bearing both nitric oxide (NO)- and hydrogen sulfide (H2S)- releasing areas. Preliminary studies have found that four NOSH variants, evaluated in eleven different human cancer cell lines, were effective in inhibiting the growth of these cell lines. NOSH-1 was also devoid of any cellular toxicity, and was comparable to aspirin in its anti-inflammatory properties.
        • Aromatase inhibition?
          • 2:16-alpha-hydroxy estrone ratios: “There is a significant positive association observed for the 2-hydroxyestrone and the 2:16 ratio among women with ER-negative/PR-negative tumors. High numbers for either was associated with triple the relative risk for this small subgroup of breast cancer patients.  Again these results are backwards from what the EMR theory predicts.  While these results don’t support the basic hypothesis that 2-hydroxyestrone lowers breast cancer risk nor that the 2 versus 16-α ratio is predictive of risk, the significant link found with hormone receptor negative breast cancer is worth noting.

         

         

         

        • July 2011: Beta-blockers: “BB intake was associated with a significantly better RFS (hazard ratio [HR], 0.52; 95% CI, 0.31 to 0.88) but not OS (P = .09). Among patients with triple-negative breast cancer (TNBC; n = 377), BB intake was associated with improved [relapse free survival] RFS (HR, 0.30; 95% CI, 0.10 to 0.87;P = .027) but not OS (HR, 0.35; 95% CI, 0.12 to 1.00;P = .05).”
        • risk of TNBC is worse in West Virginia….
          • Don’t do things the way women in W.  Virginia do.

         

         

         

        J Nutr. 2011 Aug 31. [Epub ahead of print]

        Whole Blueberry Powder Modulates the Growth and Metastasis of MDA-MB-231 Triple Negative Breast Tumors in Nude Mice.

        Adams LS, Kanaya N, Phung S, Liu Z, Chen S.

        Source

        Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, Duarte, CA.

        Abstract

        Previous studies in our laboratory demonstrated that blueberry (BB) extract exhibited antitumor activity against MDA-MB-231 triple negative breast cancer (TNBC) cells and decreased metastatic potential in vitro. The current study tested 2 doses of whole BB powder, 5 and 10% (wt:wt) in the diet, against MDA-MB-231 tumor growth in female nude mice. In this study, tumor volume was 75% lower in mice fed the 5% BB diet and 60% lower in mice fed the 10% BB diet than in control mice (P ≤ 0.05). Tumor cell proliferation (Ki-67) was lower in the 5 and 10% BB-fed mice and cell death (Caspase 3) was greater in the 10% BB-fed mice compared to control mice (P ≤ 0.05). Gene analysis of tumor tissues from the 5% BB-fed mice revealed significantly altered expression of genes important to inflammation, cancer, and metastasis, specifically, Wnt signaling, thrombospondin-2, IL-13, and IFNγ. To confirm effects on Wnt signaling, analysis of tumor tissues from 5% BB-fed mice revealed lower β-catenin expression and glycogen synthase kinase-3β phosphorylation with greater expression of the β-catenin inhibitory protein adenomatous polyposis coli compared to controls. A second study tested the ability of the 5% BB diet to inhibit MDA-MB-231-luc-D3H2LN metastasis in vivo. In this study, 5% BB-fed mice developed 70% fewer liver metastases (P = 0.04) and 25% fewer lymph node metastases (P = 0.09) compared to control mice. This study demonstrates the oral antitumor and metastasis activity of whole BB powder against TNBC in mice.

        PMID: 21880954 [PubMed - as supplied by publisher]

         

         

        Cancer Res. 2010 May 1;70(9):3594-605. Epub 2010 Apr 13.

        Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway.

        Adams LS, Phung S, Yee N, Seeram NP, Li L, Chen S.

        Source

        Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.

        Abstract

        Dietary phytochemicals are known to exhibit a variety of anticarcinogenic properties. This study investigated the chemopreventive activity of blueberry extract in triple-negative breast cancer cell lines in vitro and in vivo. Blueberry decreased cell proliferation in HCC38, HCC1937, and MDA-MB-231 cells with no effect on the nontumorigenic MCF-10A cell line. Decreased metastatic potential of MDA-MB-231 cells by blueberry was shown through inhibition of cell motility using wound-healing assays and migration through a polyethylene terephthalate membrane. Blueberry treatment decreased the activity of matrix metalloproteinase-9 and the secretion of urokinase-type plasminogen activator while increasing tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 secretion in MDA-MB-231 conditioned medium as shown by Western blotting. Cell signaling pathways that control the expression/activation of these processes were investigated via Western blotting and reporter gene assay. Treatment with blueberry decreased phosphatidylinositol 3-kinase (PI3K)/AKT and NFkappaB activation in MDA-MB-231 cells, where protein kinase C and extracellular signal-regulated kinase (ERK) were not affected. In vivo, the efficacy of blueberry to inhibit triple-negative breast tumor growth was evaluated using the MDA-MB-231 xenograft model. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry-treated mice, where apoptosis (caspase-3 expression) was increased compared with controls. Immunohistochemical analysis of tumors from blueberry-fed mice showed decreased activation of AKT and p65 NFkappaB signaling proteins with no effect on the phosphorylation of ERK. These data illustrate the inhibitory effect of blueberry phytochemicals on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFkappaB pathway.

         

         

        Mol Cancer. 2009 Oct 1;8:81.

        Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action.

        Wang S, Liu Q, Zhang Y, Liu K, Yu P, Liu K, Luan J, Duan H, Lu Z, Wang F, Wu E, Yagasaki K, Zhang G.

        Source

        Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Yantai, Shandong Province 264005, China. sw6262@yeah.net

        Abstract

        BACKGROUND:

        Breast cancer is the second leading cause of cancer related deaths among females worldwide. Berbamine (BER), a kind of bis-benzylisoquinoline alkaloid, has been used to treat clinical patients with inflammation and cancer for many years in China. The purpose of this study is to investigate the activity of BER against highly-metastatic human breast cancer and its molecular mechanisms of action.

        RESULTS:

        In our study, we found that BER inhibits growth of highly-metastatic human breast cancer cell lines MDA-MB-231 and MDA-MB-435S cells dose-dependently and time-dependently. The sera from BER-treated rats suppress the growth of MDA-MB-231 cells. BER shows synergistic effects with some existing anticancer agents such as trichostatin A (TSA, the histone deacetylase inhibitor), celecoxib (the inhibitor of COX-2), and carmofur against the growth of MDA-MB-231 cells. BER also displays the strong activity of inducing apoptosis in both estrogen receptor-negative MDA-MB-231 cells and estrogen receptor-alpha-positive MCF-7 breast cancer cells, but not in normal human mammary epithelial cell line MCF10A. BER down-regulates anti-apoptotic protein Bcl-2 levels and up-regulates pro-apoptotic protein Bax expressions in MDA-MB-231 and MDA-MB-435S cells. BER also has synergistic effects with anticancer agents trichostatin A, celecoxib and/or carmofur on reducing Bcl-2/Bax ratios and VEGF secretions in MDA-MB-231 cells. In addition, BER significantly suppresses cell migration and invasion, as well as decreases pro-MMP-9/pro-MMP-2 activation in breast cancer cells. Furthermore, BER suppresses Akt and nuclear factor kappaB signaling by reducing the phosphorylation of c-Met and Akt, and inhibiting their downstream targets such as nuclear factor kappaB p-65, Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2 on protein and/or mRNA levels in breast cancer cells.

        CONCLUSION:

        Our findings have showed that BER suppresses the growth, migration and invasion in highly-metastatic human breast cancer cells by possibly inhibiting Akt and NF-kappaB signaling with their upstream target c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2. BER has synergistic effects with anticancer agents trichostatin A, celecoxib and carmofur on inhibiting the growth of MDA-MB-231 cells and reducing the ratio of Bcl-2/Bax and/or VEGF expressions in the cancer cells. These findings suggest that BER may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer and other cancers.

        PMID: 19796390 [PubMed - indexed for MEDLINE] PMCID: PMC2765940 Free PMC Article

        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765940/?tool=pubmed

         

         

        J Pharm Sci. 2010 Jul;99(7):3266-75.

        A novel calmodulin antagonist O-(4-ethoxyl-butyl)-berbamine overcomes multidrug resistance in drug-resistant MCF-7/ADR breast carcinoma cells.

        Liu R, Zhang Y, Chen Y, Qi J, Ren S, Xushi MY, Yang C, Zhu H, Xiong D.

        Source

        State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Disease, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.

        Abstract

        Multidrug resistance (MDR) mediated by the overexpression of the drug efflux protein P-glycoprotein is one of the major obstacles to successful cancer chemotherapy. The development of safe and effective MDR-reversing agents is an important approach to addressing this problem clinically. In this study, we evaluated the P-gp-modulatory potential of O-(4-ethoxyl-butyl)-berbamine (EBB), a novel calmodulin antagonist and derivative of bisbenzylisoquinoline alkaloid, which significantly improved the chemosensitivity of P-glycoprotein-mediated multidrug-resistant cells to doxorubicin compared with the efficacy of a conventional P-glycoprotein inhibitor, verapamil. EBB not only blocked the function of P-glycoprotein confirmed by the fact that EBB increased intracellular accumulation of rhodamine 123 and doxorubicin but also inhibited the expression of P-glycoprotein actualized by downregulating P-glycoprotein. Furthermore, our results showed that cotreatment with EBB and doxorubicin resulted in marked G(2)/M arrest and apoptosis of MCF-7/ADR cells, accompanied by down-regulation of the proteins cdc2/p34 and cyclin B1 and increased the levels of calcium ions. Taken together, these results suggest that cotreatment with EBB and doxorubicin could strongly potentiate the antitumor activity of doxorubicin, thus may have significant clinical application in cancer chemotherapy.

        (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

        PMID: 20112430 [PubMed - indexed for MEDLINE]

         

         

        J Agric Food Chem. 2012 Sep 26;60(38):9649-58. Epub 2012 Sep 14.

        Berberine, an isoquinoline alkaloid, inhibits the metastatic potential ofbreast cancer cells via Akt pathway modulation.

        Kuo HPChuang TCTsai SCTseng HHHsu SCChen YCKuo CLKuo YHLiu JYKao MC.

        Source

        Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.

        Abstract

        Berberine (BBR) is a natural alkaloid with significant antitumor activities against many types ofcancer cells. In this study, we investigated the molecular mechanisms by which BBR repressed the metastatic potential of breast cancer cells. BBR was found to downregulate the enzymatic activities and expression levels of matrix metalloproteinases 2 and 9 (MMP2 and MMP9, respectively). The BBR-mediated suppression of MMP2 and MMP9 involved the inhibition of the Akt/nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) signaling pathways. Furthermore, BBR repressed the expression of the Akt protein by modulating the mRNA expression level and protein degradation of Akt. In conclusion, this study suggests that BBR can reduce the metastatic potential of highly metastatic breast cancer cells and may be a useful adjuvant therapeutic agent in the treatment of breast cancer by targeting the Akt pathway.

        PMID:

         

        22950834

         

        [PubMed - in process]

         

         

        Int J Cancer. 2005 Sep 20;116(5):793-8.

        The inhibitory effect of flaxseed on the growth and metastasis of estrogen receptor negative human breast cancer xenograftsis attributed to both its lignan and oil components.

        Wang L, Chen J, Thompson LU.

        Source

        Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

        Abstract

        Our previous studies have shown that dietary flaxseed (FS) can reduce the growth and metastasis of human estrogen receptor negative (ER-) breast cancer in nude mice. The aims of our study were to determine (i) whether the tumor inhibitory effect of FS was due to its oil (FO), lignan secoisolariciresinol diglycoside (SDG), or both components, and (ii) whether the effect on tumor growth was related to increased lipid peroxidation. Athymic nude mice were orthotopically injected with ER- breast cancer cells (MDA-MB-435) and 8 weeks later were fed either the basal diet (BD) or BD supplemented with 10% FS, SDG, FO, or combined SDG and FO (SDG + FO) for 6 weeks. The SDG and FO levels were equivalent to the amounts in the 10% FS. Compared to the BD group, the tumor growth rate was significantly lower (p < 0.05) in the FS, FO, and SDG + FO groups, in concordance with decreased cell proliferation and increased apoptosis; however, these did not significantly relate to the lipid peroxidation, indexed as malonaldehyde (MDA), in the primary tumors. Lung metastasis incidence was reduced (16-70%) by all treatments, significantly in the FS and SDG + FO groups. The distant lymph node metastasis was significantly decreased (52%) only in the FO group. Although the total metastasis incidence was lowered (42%) significantly only in the SDG + FO group, all treatment groups did not differ significantly. In conclusion, FS reduced the growth and metastasis of established ER- human breast cancer in part due to its lignan and FO components, and not to lipid peroxidation.

         

        Mol Nutr Food Res. 2010 Mar;54(3):415-25.

        Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF-7 tumor growth through estrogen receptor- and growth factor-signaling pathways.

        Saggar JK, Chen J, Corey P, Thompson LU.

        Source

        Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

        Abstract

        This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels, and potential mechanisms of action. In a 2 x 2 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER-mediated (ER-alpha, ER-beta, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor-mediated (epidermal growth factor receptor, human epidermal growth factor receptor-2, insulin-like growth factor receptor-1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM-treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM-treated tumors but FO was more effective. The mechanisms involve both the ER- and growth factor-signaling pathways.

        PMID: 19904759

         

        Bioorg Med Chem. 2013 Apr 15;21(8):2305-13. doi: 10.1016/j.bmc.2013.02.015. Epub 2013 Feb 22.

        A novel metformin derivative, HL010183, inhibits proliferation and invasion of triple-negative breast cancer cells.

        Koh MLee JCMin CMoon A.

        Source

        College of Pharmacy, Duksung Women's University, Seoul 132-714, Republic of Korea.

        Abstract

        Mounting evidence suggests that metformin (N,N-dimethylbiguanide), a widely prescribed drug for the treatment of type II diabetes, exerts an anti-tumor effect on several cancers includingbreast cancer. Breast cancer has been estimated as one of the most commonly diagnosed types of cancer among women. In particular, triple-negative breast cancers are associated with poor prognosis and metastatic growth. In the present study, we synthesized a novel metforminderivative 5 (HL010183) and metformin salts, 9a, 9b, and 9c (metformin gamma-aminobutyric acid (GABA) salt, metformin pregabalin salt and metformin gabapentin salt), which exerted more potent inhibitory effects on the proliferation and invasiveness of Hs578T triple-negative breastcarcinoma cells than metformin. Importantly, 5 showed approximately 100-fold more potent effects compared to metformin. In a triple-negative breast cancer xenograft model, 5 showed a comparable degree of inhibitory effect on in vivo tumor growth at the 100mg/kg dose to that ofmetformin at 500mg/kg. Our results clearly demonstrate that 5 exerts a potent anti-tumor effect both in vitro and in vivo, paving the way for a strategy for treatment of triple-negative breast cancer.

        Copyright © 2013 Elsevier Lt

         

         

        J Health Care Poor Underserved. 2013 Feb;24(1 Suppl):93-103. doi: 10.1353/hpu.2013.0044.

        Metformin induces a senescence-associated gene signature in breast cancer cells.

        Williams CCSingleton BALlopis SDSkripnikova EV.

        Source

        Division of Basic Pharmaceutical Sciences, Xavier University of Louisiana, School of Pharmacy, 1 Drexel Drive, New Orleans, LA 70125, USA. cwilli35@xula.edu

        Abstract

        Diabetic patients taking metformin have lower incidence of breast cancer than those taking other anti-diabetic medications. Additionally, triple negative breast cancer (TNBC), a form of breast cancer disproportionately afflicting premenopausal African American women, shows atypical susceptibility to metformin's antiproliferative effect. The mechanisms involved in metformin's function in TNBC has not yet been fully elucidated. Therefore, we sought to identify pathways regulated by metformin in using the MDA-MB-468 TNBC cell model. Metformin dose-dependently caused apoptosis, decreased cell viability, and induced cell morphology/chromatin condensation consistent with the permanent proliferative arrest. Furthermore, gene expression arrays revealed that metformin caused expression of stress markers DDIT3, CYP1A1,and GDF-15 and a concomitant reduction in PTGS1 expression. Our findings show that metformin may affect the viability and proliferative capacity of TNBC by inducing an antiproliferative gene signature, and that metformin may be effective in the treatment/prevention of TNBC.

        PMID:

         

        23395946

         

        [PubMed - in process]

         

         

        Cancer. 2012 Mar 1;118(5):1202-11. doi: 10.1002/cncr.26439. Epub 2011 Jul 28.

        Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer.

        Bayraktar S, Hernadez-Aya LF, Lei X, Meric-Bernstam F, Litton JK, Hsu L, Hortobagyi GN, Gonzalez-Angulo AM.

        Source

        Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.

        Abstract

        BACKGROUND:

        Recent observational studies have shown that metformin use in diabetic patients decreases both cancer incidence and mortality. Metformin use is also independently predictive of pathologic complete response. In the current study, the authors explored the association between metformin use and survival outcomes in patients with triple receptor-negative breast cancer (TNBC) who were receiving adjuvant chemotherapy.

        METHODS:

        The Breast Cancer Management System database of The University of Texas MD Anderson Cancer Center identified 1448 women who received adjuvant chemotherapy for TNBC between 1995 and 2007. Patients were categorized by diabetes status and metformin use. The Kaplan-Meier product-limit method was used to calculate distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). Cox proportional hazards models were fit to determine the association between metformin use and survival outcomes.

        RESULTS:

        The study cohort was comprised of 63 diabetic patients receiving treatment with metformin, 67 diabetic patients not receiving metformin, and 1318 nondiabetic patients. Patients in the diabetic groups tended to be older (P = .005); more diabetic patients were postmenopausal (P = .0007), black (P = .0001), and obese (P < .0001). At a median follow-up of 62 months, there were no significant differences with regard to 5-year DMFS (P = .23), RFS (P = .38), and OS (P = .58) between the 3 groups. Compared with the metformin group, patients who did not receive metformin (hazard ratio [HR], 1.63; 95% confidence interval [95% CI], 0.87-3.06 [P = .13]) and nondiabetic patients (HR, 1.62; 95% CI, 0.97-2.71 [P = .06]) tended to have a higher risk of distant metastases.

        CONCLUSIONS:

        The findings of the current study suggest that metformin use during adjuvant chemotherapy does not significantly impact survival outcomes in diabetic patients with TNBC.

        Copyright © 2011 American Cancer Society.

        PMID: 21800293 [PubMed - indexed for MEDLINE]

         

        Cancer. 2012 Mar 1;118(5):1202-11. doi: 10.1002/cncr.26439. Epub 2011 Jul 28.

        Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer.

        Bayraktar S, Hernadez-Aya LF, Lei X, Meric-Bernstam F, Litton JK, Hsu L, Hortobagyi GN, Gonzalez-Angulo AM.

        Source

        Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.

        Abstract

        BACKGROUND:

        Recent observational studies have shown that metformin use in diabetic patients decreases both cancer incidence and mortality. Metformin use is also independently predictive of pathologic complete response. In the current study, the authors explored the association between metformin use and survival outcomes in patients with triple receptor-negative breast cancer (TNBC) who were receiving adjuvant chemotherapy.

        METHODS:

        The Breast Cancer Management System database of The University of Texas MD Anderson Cancer Center identified 1448 women who received adjuvant chemotherapy for TNBC between 1995 and 2007. Patients were categorized by diabetes status and metformin use. The Kaplan-Meier product-limit method was used to calculate distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). Cox proportional hazards models were fit to determine the association between metformin use and survival outcomes.

        RESULTS:

        The study cohort was comprised of 63 diabetic patients receiving treatment with metformin, 67 diabetic patients not receiving metformin, and 1318 nondiabetic patients. Patients in the diabetic groups tended to be older (P = .005); more diabetic patients were postmenopausal (P = .0007), black (P = .0001), and obese (P < .0001). At a median follow-up of 62 months, there were no significant differences with regard to 5-year DMFS (P = .23), RFS (P = .38), and OS (P = .58) between the 3 groups. Compared with the metformin group, patients who did not receive metformin (hazard ratio [HR], 1.63; 95% confidence interval [95% CI], 0.87-3.06 [P = .13]) and nondiabetic patients (HR, 1.62; 95% CI, 0.97-2.71 [P = .06]) tended to have a higher risk of distant metastases.

        CONCLUSIONS:

        The findings of the current study suggest that metformin use during adjuvant chemotherapy does not significantly impact survival outcomes in diabetic patients with TNBC.

        Copyright © 2011 American Cancer Society.

        PMID: 21800293 [PubMed - indexed for MEDLINE] PMCID: PMC3207034 [Available on 2013/3/1]

         

        Cell Cycle. 2012 Jan 15;11(2):367-76. doi: 10.4161/cc.11.2.18813. Epub 2012 Jan 15.

        Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers.

        Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, Wahdan-Alaswad R, Thor AD.

        Source

        Department of Pathology, University of Colorado Denver, Denver, CO, USA.

        Abstract

        A distinct group of breast cancers, called "basal" or "triple-negative" (TN) cancers express both basal cytokeratins and the epidermal growth factor receptor, but fail to express estrogen receptors, progesterone receptors or HER2 and have stem-like or mesenchymal features. They are particularly aggressive, are frequently chemo-resistant, with p53 mutation, up-regulation of IL-6 and Stat3. Because TN cells are particularly sensitive to the anti-diabetic agent metformin, we hypothesized that it may target JAK2/Stat3 signaling. The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines. Metformin's effects were also studied in sublines with forced over-expression of constitutively active (CA) Stat3, as well as lines with stable knockdown of Stat3. Metformin inhibited Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines. CA-Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of metformin upon growth inhibition and apoptosis induction. A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis. An mTOR inhibitor showed no significant interaction with metformin. In summary, Stat3 is a critical regulator of metformin action in TN cancer cells, providing the potential for enhancing metformin's efficacy in the clinical setting.

        PMID: 22189713 [PubMed - indexed for MEDLINE]

         

         

        Oncol Rep. 2011 Jan;25(1):135-40.

        The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells.

        Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Lopez-Bonet E, Menendez JA.

        Source

        Catalan Institute of Oncology, Dr Josep Trueta University Hospital of Girona, Girona, Catalonia, Spain.

        Abstract

        CD24, a mucin-like adhesion molecule that enhances the metastatic potential of malignant cells, has been suggested to be a marker of poor prognosis in breast carcinomas. The tumor-initiating potential of CD44posCD24pos cell populations has been recently recognized and, accordingly, distant metastases are largely composed of CD24-positive cells in breast cancer patients refractory to treatment. Therefore, new therapeutic strategies aimed at down-regulating CD24 may negatively regulate the dissemination of tumor cells and formation of metastasis. Here, we reveal that suppression of CD24 protein expression is a crucial event in the molecular mechanisms underlying the growth-inhibitory effects of the anti-diabetic drug metformin in MDA-MB-468 triple-negative (basal-like) breast cancer cells. First, we confirmed that, among the different molecular classes of breast cancer, basal-like breast cancer cells were significantly more sensitive to the growth-inhibitory effects of metformin. Second, we observed a positive correlation between the growth inhibitory activity of metformin and the relative enrichment in cells bearing the CD44posCD24pos immunophenotype. Third, high-content indirect immunofluorescence imaging assays revealed that CD24 protein levels were drastically decreased in the presence of growth-inhibitory concentrations of metformin. Fourth, to preliminary assess the clinical relevance of metformin's anti-CD24 effects we took advantage of the recently developed ROCK online interface (http://rock.icr.ac.uk/), a publicly accessible portal that allows rapid integration of breast cancer functional and molecular profiling datasets. When we evaluated the impact of CD24 expression on distant metastasis-free survival (DMFS) in microarray gene expression breast cancer datasets, Kaplan-Meier survival analyses and log-rank tests comparing DMSF for CD24-high and CD24-low breast carcinomas revealed that patients with CD24-high tumors tended to have a shorter DMFS. These findings, altogether, suggest that the ability of metformin to suppress the oncogene, metastasis promoter and breast cancer stem cell marker CD24 may open a novel molecular avenue in the therapeutic management of highly-metastastic subgroups of triple-negative (basal-like) breast cancers naturally enriched with CD44posCD24pos tumor-initiating cell populations.

        PMID: 21109968 [PubMed - indexed for MEDLINE]

         

        Breast Cancer Res Treat. 2010 Sep;123(2):333-44. doi: 10.1007/s10549-009-0647-z. Epub 2009 Nov 22.

        Dietary energy availability affects primary and metastatic breast cancer andmetformin efficacy.

        Phoenix KNVumbaca FFox MMEvans RClaffey KP.

        Source

        Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3501, USA.

        Abstract

        Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reducecancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events.

        PMID:

         

        20204498

         

        [PubMed - indexed for MEDLINE] 

        PMCID:

         

        PMC2888909

         Free PMC Article

         

         

        Cell Cycle. 2009 Sep 1;8(17):2681. Epub 2009 Sep 1.

        Expanding the arsenal: metformin for the treatment of triple-negative breast cancer?

        Jiralerspong S, Gonzalez-Angulo AM, Hung MC.

        Source

        MD Anderson Cancer Center, Houston, TX, USA.

        Comment on

        PMID: 19717981 [PubMed - indexed for MEDLINE] Free full text

         

        Cell Cycle. 2012 Jan 15;11(2):367-76. Epub 2012 Jan 15.

        Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers.

        Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, Wahdan-Alaswad R, Thor AD.

        Source

        Department of Pathology, University of Colorado Denver, Denver, CO, USA.

        Abstract

        A distinct group of breast cancers, called "basal" or "triple-negative" (TN) cancers express both basal cytokeratins and the epidermal growth factor receptor, but fail to express estrogen receptors, progesterone receptors or HER2 and have stem-like or mesenchymal features. They are particularly aggressive, are frequently chemo-resistant, with p53 mutation, up-regulation of IL-6 and Stat3. Because TN cells are particularly sensitive to the anti-diabetic agent metformin, we hypothesized that it may target JAK2/Stat3 signaling. The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines. Metformin's effects were also studied in sublines with forced over-expression of constitutively active (CA) Stat3, as well as lines with stable knockdown of Stat3. Metformin inhibited Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines. CA-Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of metformin upon growth inhibition and apoptosis induction. A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis. An mTOR inhibitor showed no significant interaction with metformin. In summary, Stat3 is a critical regulator of metformin action in TN cancer cells, providing the potential for enhancing metformin's efficacy in the clinical setting.

        PMID: 22189713 [PubMed - indexed for MEDLINE]

         

        Oncol Rep. 2011 Jan;25(1):135-40.

        The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells.

        Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Lopez-Bonet E, Menendez JA.

        Source

        Catalan Institute of Oncology, Dr Josep Trueta University Hospital of Girona, Girona, Catalonia, Spain.

        Abstract

        CD24, a mucin-like adhesion molecule that enhances the metastatic potential of malignant cells, has been suggested to be a marker of poor prognosis in breast carcinomas. The tumor-initiating potential of CD44posCD24pos cell populations has been recently recognized and, accordingly, distant metastases are largely composed of CD24-positive cells in breast cancer patients refractory to treatment. Therefore, new therapeutic strategies aimed at down-regulating CD24 may negatively regulate the dissemination of tumor cells and formation of metastasis. Here, we reveal that suppression of CD24 protein expression is a crucial event in the molecular mechanisms underlying the growth-inhibitory effects of the anti-diabetic drug metformin in MDA-MB-468 triple-negative (basal-like) breast cancer cells. First, we confirmed that, among the different molecular classes of breast cancer, basal-like breast cancer cells were significantly more sensitive to the growth-inhibitory effects of metformin. Second, we observed a positive correlation between the growth inhibitory activity of metformin and the relative enrichment in cells bearing the CD44posCD24pos immunophenotype. Third, high-content indirect immunofluorescence imaging assays revealed that CD24 protein levels were drastically decreased in the presence of growth-inhibitory concentrations of metformin. Fourth, to preliminary assess the clinical relevance of metformin's anti-CD24 effects we took advantage of the recently developed ROCK online interface (http://rock.icr.ac.uk/), a publicly accessible portal that allows rapid integration of breast cancer functional and molecular profiling datasets. When we evaluated the impact of CD24 expression on distant metastasis-free survival (DMFS) in microarray gene expression breast cancer datasets, Kaplan-Meier survival analyses and log-rank tests comparing DMSF for CD24-high and CD24-low breast carcinomas revealed that patients with CD24-high tumors tended to have a shorter DMFS. These findings, altogether, suggest that the ability of metformin to suppress the oncogene, metastasis promoter and breast cancer stem cell marker CD24 may open a novel molecular avenue in the therapeutic management of highly-metastastic subgroups of triple-negative (basal-like) breast cancers naturally enriched with CD44posCD24pos tumor-initiating cell populations.

        PMID: 21109968 [PubMed - indexed for MEDLINE]

         

        Oncol Rep. 2012 Jul 26. doi: 10.3892/or.2012.1936. [Epub ahead of print]

        BreastDefend™ prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer.

        Jiang J, Thyagarajan-Sahu A, Loganathan J, Eliaz I, Terry C, Sandusky GE, Sliva D.

        Source

        Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, IN 46202, USA.

        Abstract

        We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast-to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers.

        PMID: 22842551 [PubMed - as supplied by publisher]

         

        J BUON. 2011 Jul-Sep;16(3):569.

        Vitamin D intake may be effective in the management of triple-negative breast cancer.

        Harputluoglu H, Dizdar O, Karaahmet F, Altundag K.

        PMID: 22006770 [PubMed - indexed for MEDLINE]

         

        J Steroid Biochem Mol Biol. 2012 Sep 18. pii: S0960-0760(12)00166-5. doi: 10.1016/j.jsbmb.2012.09.010. [Epub ahead of print]

        Associations between vitamin D deficiency and risk of aggressive breast cancer in African-American women.

        Yao S, Ambrosone CB.

        Source

        Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, United States.

        Abstract

        Although breast cancer incidence in the US is highest for women of European ancestry (EA), women of African ancestry (AA) have higher incidence of cancer diagnosed before age 40 and tumors with more aggressive features (high grade and negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2)), which precludes targeted therapies and leads to poorer outcomes. It is unclear what underlies these disparities. It has been hypothesized that dark skin with high melanin content is the ancestral skin color of origin, with adaptation to northern environs resulting in lighter skin. Although intense sunlight in sub-Saharan Africa may compensate for low sun absorption through skin, an urban or western lifestyle may result in less synthesis of vitamin D with higher skin pigmentation. Laboratory and preclinical data indicate that vitamin D is involved in preventing breast carcinogenesis and progression. Vitamin D receptor (VDR) knock-out mice are more likely to develop tumors that are ER-negative, and we have shown that serum levels of 25OHD are lowest among EA women with triple-negative tumors (negative for ER, PR and HER2); and among non-cancer patients, vitamin D levels are lower in AAs than in EAs. Thus, it is plausible to hypothesize that low vitamin D levels could be associated with the higher prevalence of more aggressive tumors among AA women. In this paper, we review the current literature on vitamin D and aggressive breast cancer subtypes, discuss vitamin D in AA women from a perspective of evolution and adaption, and examine the potential role of vitamin D in cancer racial disparities. We present our recently published data showing two single nucleotide polymorphisms in vitamin D catabolic enzyme CYP24A1 associated with higher risk of estrogen ER-negative risk in AA than in EA women. The relationship of vitamin D with breast cancer risk may be subtype-specific, with emerging evidence of stronger effects of vitamin D for more aggressive breast cancer, particularly in women of African ancestry.

         

        Copyright © 2012. Published by Elsevier Ltd.

         

         

        Anticancer Res. 2012 Jan;32(1):249-57.

        1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation.

        Lopes N, Carvalho J, Durães C, Sousa B, Gomes M, Costa JL, Oliveira C, Paredes J, Schmitt F.

        Source

        IPATIMUP, Institute of Molecular Pathology and Immunology of University of Porto, Porto, Portugal.

        Abstract

        BACKGROUND:

        The triple-negative subgroup of breast cancer includes a cluster of tumors exhibiting low E-cadherin expression (metaplastic carcinomas). In several cancer models, 1 alpha,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)) induces differentiation by increasing E-cadherin expression. The Vitamin D receptor (VDR) was evaluated as a possible therapeutic target for metaplastic carcinomas and 1α,25(OH)(2)D(3) effects as a differentiating agent in triple-negative breast cancer cells were assessed.

         

        MATERIALS AND METHODS:

        Metaplastic carcinomas were assessed for VDR expression by immunohistochemistry; differences in E-cadherin expression in triple-negative breast cancer cells were evaluated by real-time PCR, western blotting and Cadherin 1 (CDH1) methylation status.

         

        RESULTS:

        Most of the metaplastic carcinomas were positive for VDR expression. Furthermore, 1α,25(OH)(2)D(3) promoted differentiation of MDA-MB-231 cells by inducing de novo E-cadherin expression, an effect that was time- and dose-dependent. Also, E-cadherin expression was due to promoter demethylation.

         

        CONCLUSION:

        Metaplastic carcinomas may respond to 1α,25(OH)(2)D(3), since they express VDR and 1α,25(OH)(2)D(3) induces de novo E-cadherin expression in breast cancer cells by promoter demethylation.

         

        PMID: 22213313 [PubMed - indexed for MEDLINE]

        Cases J. 2009 Jul 21;2:8390.

        Triple negative breast cancer patients presenting with low serum vitamin D levels: a case series.

        Rainville C, Khan Y, Tisman G.

        Source

        A Medical Corporation 13025 Bailey Street, Suite A, Whittier, CA 90601 USA. christa324@gmail.com

        Abstract

        INTRODUCTION:

        Serum vitamin D levels measured as 25-hydroxyvitamin D have been shown to be low in cancer patients, including breast cancer patients. However, the vitamin D status has yet to be studied in different breast cancer phenotypes: luminal A, luminal B, HER2+/ER-, and triple negative comprising the majority of basal-like.

         

        CASE PRESENTATION:

        Fifteen triple-negative breast cancer patients have presented to our medical oncology office in the last five years. Thirteen of these fifteen patients (87%) were found to be vitamin D deficient, defined as serum 25(OH)D less than 80 nmol/L, prior to initiation of adjuvant therapy. Ninety-one breast cancer patients from our office were classified as: luminal A (ER+ &/or PR+ and HER2-), luminal B (ER+ &/or PR+ and HER2+), HER2+/ER- (ER-, PR-, and HER2+), and triple-negative or basal-like (ER-, PR-, and HER2-). A normal mean was found from 78 volunteers. The breast cancer patients were found to be statistically different than the normal population. The triple-negative phenotype was found to be the most statistically different than the normal population.

         

        CONCLUSION:

        The triple-negative breast cancer phenotype has the lowest average vitamin D level and the highest percentage of patients that are vitamin D deficient. These data suggests that low vitamin D levels are characteristic of the triple-negative phenotype.

         

        Ann Surg Oncol. 2011 Jul;18(7):1830-6. doi: 10.1245/s10434-010-1465-6. Epub 2010 Dec 14.

        Vitamin D deficiency is correlated with poor outcomes in patients with luminal-type breast cancer.

        Kim HJLee YMKo BSLee JWYu JHSon BHGong GYKim SBAhn SH.

        Source

        Department of Surgery, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.

        Abstract

        PURPOSE:

        Vitamin D deficiency may be an indicator of poor prognosis in patients with breast cancer before surgery. We investigated the association between serum vitamin D concentration and breast cancer prognosis according to intrinsic cancer subtypes.

        METHODS:

        From June to December 2006, serum 25-OHD was measured in 310 Korean women with breast cancer who were treated at the Asan Medical Center, Korea. Clinicopathologic data were examined to determine the prognostic effects of serum 25-OHD. Expression of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (Her2) were measured using tissue microarrays. Patients were classified with luminal A, luminal B, Her2-enriched, or basal-like subtypes of breast cancer.

        RESULTS:

        Mean patient age was 48.7 years, and mean serum 25-OHD concentration was 31.4 ± 16.1 ng/ml. The 25-OHD levels were deficient (< 20 ng/ml) in 75 patients (24.2%), insufficient (20-29 ng/ml) in 95 (30.6%), and sufficient (30-150 ng/ml) in 140 (45.2%). Women with deficient 25-OHD levels were at increased risk of recurrence compared with those with sufficient vitamin Dlevels (P = 0.002). The 25-OHD concentration was inversely associated with prognosis of patients with cancer of the luminal A (P = 0.012) and luminal B subtypes (P =0.023), but not with the prognosis of patients with Her2/neu-enriched (P = 0.245) or triple-negative (P = 0.879)cancer subtypes. This association remained valid after adjustment for age, tumor size, nodal status, and estrogen receptor status (hazards ratio = 3.97; 95% confidence interval = 1.77-9.61).

        CONCLUSIONS:

        Vitamin D deficiency may be associated with poor outcomes in patients with luminal-type breast cancer.

        PMID:

         

        21573699

         

        [PubMed - indexed for MEDLINE] 

        PMCID:

         

        PMC3115047

         Free PMC Article

         

         

        Mol Med Report. 2012 Dec;6(6):1267-70. doi: 10.3892/mmr.2012.1103. Epub 2012 Sep 26.

        Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EGFR expression.

        Sun XD, Liu XE, Huang DS.

        Source

        Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.

        Abstract

        Curcumin is the major component of the spice turmeric, extracted from the rhizomes of the plant Curcuma longa. It exerts a number of therapeutic effects, including the inhibition of cancer cell proliferation. However, the anti-carcinogenic mechanism of curcumin has not been fully elucidated. Triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/EGFR2), is an aggressive breast cancer phenotype with a poor prognosis. In this study, we investigated the effects of curcumin on triple-negative breast cancer cells and the possible molecular mechanisms. The MDA-MB-231 TNBC cells were treated with curcumin, the growth inhibition ratio of the cells was measured by MTT assay, apoptosis was detected by flow cytometry and the expression levels of extracellular regulated protein kinase (ERK1/2), pERK1/2, EGFR and pEGFR were detected by western blotting. After treatment with different concentrations of curcumin, the growth inhibition rates of the MDA-MB-231 breast cancer cells of the 30 µmol/ml curcumin-treated group were significantly different from those of the other groups. The level of apoptosis of the curcumin-treated group (26.34%) was significantly different from that of the control group (2.76%). The expression levels of pERK1/2 and pEGFR in the curcumin-treated group were significantly decreased compared with those of the control group. These results indicate that curcumin is able to inhibit the proliferation of TNBC cells. Inhibition of the EGFR signaling pathway is the likely underlying molecular mechanism.

        PMID: 23023821 [PubMed - in process]

         

         

        Breast Cancer (Auckl). 2010 Feb 16;4:1-3.

        Targeting DNA damage and repair by curcumin.

        Ji Z.

        Source

        Wellman Center for Photomedicine and the Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA.

        Abstract

        Curcumin is a compound with anti-tumor effects in a tolerable dose. A recent paper by Rowe et al described that curcumin induced DNA damage in triple negative breast cancer cells and regulated BRCA1 protein expression and modification.1 Related research and potential use of curcumin will be discussed in this article.

        PMID: 20697527 [PubMed] PMCID: PMC2914279 Free PMC Article

         

        Breast Cancer (Auckl). 2009 Sep 2;3:61-75.

        Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin.

        Rowe DL, Ozbay T, O'Regan RM, Nahta R.

        Source

        Departments of Pharmacology.

        Abstract

        In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.

        PMID: 19809577 [PubMed] PMCID: PMC2756684 Free PMC Article

         

        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756684/?tool=pubmed

         

         

        Cancer Lett. 2011 Sep 1;308(1):43-53. Epub 2011 May 13.

        Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer.

        Wu JOmene CKarkoszka JBosland MEckard JKlein CBFrenkel K.

        Source

        Dept. of Environmental Medicine, NYU School of Medicine, New York, 10016, USA.

        Abstract

        Breast cancer (BC) patients use alternative and natural remedies more than patients with other malignancies. Specifically, 63-83% use at least one type of alternative medicine and 25-63% use herbals and vitamins. Propolis is a naturopathic honeybee product, and CAPE (caffeic acid phenethyl ester), is a major medicinal component of propolis. CAPE, in a concentration dependent fashion, inhibits MCF-7 (hormone receptor positive, HR+) and MDA-231 (a model of triple negative BC (TNBC) tumor growth, both in vitro and in vivo without much effect on normal mammary cells and strongly influences gene and protein expression. It induces cell cycle arrest, apoptosis and reduces expression of growth and transcription factors, including NF-êB. Notably, CAPE down-regulates mdr-1 gene, considered responsible for the resistance of cancer cells to chemotherapeutic agents. Further, CAPE dose-dependently suppresses VEGF formation by MDA-231 cells and formation of capillary-like tubes by endothelial cells, implicating inhibitory effects on angiogenesis. In conclusion, our results strongly suggest that CAPE inhibits MDA-231 and MCF-7 human breastcancer growth via its apoptotic effects, and modulation of NF-êB, the cell cycle, and angiogenesis.

        Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

        --

         

        Invest New Drugs. 2012 Aug;30(4):1279-88. Epub 2011 May 3.

        Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells.

        Omene CO, Wu J, Frenkel K.

        Source

        Department of Medicine, NYU School of Medicine, 550 First Avenue, BCD, Rm 556, New York, NY 10016, USA. coral.omene@nyumc.org

        Abstract

        Cancer stem cells (CSC) are chemoresistant and implicated in tumor recurrence, metastasis and high patient mortality; thus substances impairing CSC activity, could be invaluable as novel cancer therapeutics. We previously showed that CAPE (caffeic acid phenethyl ester), a component of propolis, a honeybee product, inhibits growth of MDA-MB-231 (MDA-231) cells, mdr gene expression, NF-κB, EGFR, and VEGF. We hypothesized that CAPE also acts by interfering with CSC-mediated effects. We isolated breast CSC (bCSC) from MDA-231 cells, a model of human triple-negative breast cancer, and mouse xenografts. bCSC grow as mammospheres (MMS) and when dissociated into single cells, form MMS again, a sign of self-renewal. bCSC exhibited the characteristic CD44(+)/CD24(-/low) phenotype and generated progenitors in the presence of serum, a CSC trait responsible for regenerating tumor mass. CAPE caused dose-dependent bCSC self-renewal inhibition and progenitor formation. Clonal growth on soft agar was inhibited dose-dependently, but apoptosis was not induced as determined by Annexin-V/PI assay. Instead, bCSC were noted to significantly progress from a quiescent cell cycle state in G0/G1 (82%), S phase (12%) to a cycling state with an increase in S phase (41%) and subsequent decrease in G0/G1 (54%). Treatment of bCSC with CAPE (4.5-days) decreased CD44 levels by 95%, while another cell population containing 10-100-fold lower CD44 content concurrently increased. Results suggest that CAPE causes pronounced changes in bCSC characteristics manifested by inhibition of self renewal, progenitor formation, clonal growth in soft agar, and concurrent significant decrease in CD44 content, all signs of decreased malignancy potential.

        PMID: 21537887 [PubMed - in process] PMCID: PMC3388256 Free PMC Article

         

        Med Oncol. 2011 Dec;28(4):1308-10. Epub 2010 Jul 29.

        Aspirin intake may prevent metastasis in patients with triple-negative breast cancer.

        Ararat E, Sahin I, Altundag K.

        Source

        Department of Medical Oncology, Hacettepe University Institute of Oncology, Sihhiye, 06100, Ankara, Turkey.

        PMID: 20668965 [PubMed - indexed for MEDLINE]

         

        Biochem Pharmacol. 2012 Mar 15;83(6):723-32. Epub 2011 Dec 24.

        Hydrogen sulfide-releasing aspirin suppresses NF-κB signaling in estrogen receptor negative breast cancer cells in vitro and in vivo.

        Chattopadhyay MKodela RNath NBarsegian ABoring DKashfi K.

        Source

        Department of Physiology and Pharmacology, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, United States.

        Abstract

        Hormone-dependent estrogen receptor positive (ER+) breast cancers generally respond well to anti-estrogen therapy. Unfortunately, hormone-independent estrogen receptor negative (ER-) breast cancers are aggressive, respond poorly to current treatments and have a poor prognosis. New approaches and targets are needed for the prevention and treatment of ER- breast cancer. The NF-κB signaling pathway is strongly implicated in ER- tumor genesis, constituting a possible target for treatment. Hydrogen sulfide-releasing aspirin (HS-ASA), a novel and safer derivative of aspirin, has shown promise as an anti-cancer agent. We examined the growth inhibitory effect of HS-ASA via alterations in cell proliferation, cell cycle phase transitions, and apoptosis, using MDA-MB-231 cells as a model of triple negative breast cancer. Tumor xenografts in mice, representing human ER- breast cancer, were evaluated for reduction in tumor size, followed by immunohistochemical analysis for proliferation, apoptosis and expression of NF-κB. HS-ASA suppressed the growth of MDA-MB-231 cells by induction of G(0)/G(1) arrest and apoptosis, down-regulation of NF-κB, reduction of thioredoxin reductase activity, and increased levels reactive oxygen species. Tumor xenografts in mice, were significantly reduced in volume and mass by HS-ASA treatment. The decrease in tumor mass was associated with inhibition of cell proliferation, induction of apoptosis and decrease in NF-κB levels in vivo. HS-ASA has anti-cancer potential against ER- breast cancerand merits further study.

        Copyright © 2011 Elsevier Inc. All rights reserved.

         

         

        Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE. Circulating 2-hydroxy- and 16alpha-hydroxy estrone levels and risk of breast cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2008 Aug;17(8):2029-35.

         

        J Clin Oncol. 2011 Jul 1;29(19):2645-52. doi: 10.1200/JCO.2010.33.4441. Epub 2011 May 31.

        Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer.

        Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM.

        Source

        The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. amelhem@mdanderson.org

        Abstract

        PURPOSE:

        To examine the association between beta-blocker (BB) intake, pathologic complete response (pCR) rates, and survival outcomes in patients with breast cancer treated with neoadjuvant chemotherapy.

         

        PATIENTS AND METHODS:

        We retrospectively reviewed 1,413 patients with breast cancer who received neoadjuvant chemotherapy between 1995 and 2007. Patients taking BBs at the start of neoadjuvant therapy were compared with patients with no BB intake. Rates of pCR between the groups were compared using a χ² test. Cox proportional hazards models were fitted to determine the association between BB intake, relapse-free survival (RFS), and overall survival (OS).

         

        RESULTS:

        Patients who used BBs (n = 102) were compared with patients (n = 1,311) who did not. Patients receiving BBs tended to be older and obese (P < .001). The proportion of pCR was not significantly different between the groups (P = .48). After adjustment for age, race, stage, grade, receptor status, lymphovascular invasion, body mass index, diabetes, hypertension, and angiotensin-converting enzyme inhibitor use, BB intake was associated with a significantly better RFS (hazard ratio [HR], 0.52; 95% CI, 0.31 to 0.88) but not OS (P = .09). Among patients with triple-negative breast cancer (TNBC; n = 377), BB intake was associated with improved RFS (HR, 0.30; 95% CI, 0.10 to 0.87;P = .027) but not OS (HR, 0.35; 95% CI, 0.12 to 1.00;P = .05).

         

        CONCLUSION:

        In this study, BB intake was associated with improved RFS in all patients with breast cancer and in patients with TNBC. Additional studies evaluating the potential benefits of beta-adrenergic blockade on breast cancer recurrence with a focus on TNBC are warranted.

         

        Comment in

        Expanding our therapeutic options: Beta blockers for breast cancer? [J Clin Oncol. 2011]

        Targeted therapies: Using β-blockers to inhibit breast cancer progression. [Nat Rev Clin Oncol. 2011]

        PMID: 21632501 [PubMed - indexed for MEDLINE] PMCID: PMC3139371 Free PMC Article

         

         

        W V Med J. 2009 Oct;105 Spec No:54-9.

        Triple-negative breast cancer in West Virginia.

        Abraham JFlanagan MHazard HJubelirer STirona MTVona-Davis L.

        Source

        Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA.

        Abstract

        In 2007, the American Cancer Society ranked West Virginia 43rd in breast cancer incidence rates for individual states. Despite our improvements in medical care, the advanced pathological characteristics of breast cancer at diagnosis receive little attention. Consequently, we compared the changing pattern of early breast cancer in several cohort studies conducted at regional medical centers in West Virginia. The data used in this analysis was derived from 320 women presenting at West Virginia University Hospital (WVUH) in Morgantown between 1999 and 2004, with a diagnosis of invasive breast cancer. Details of age, tumor size and axillary lymph node status were compared with tumor registry information published from a cohort study of 191 patients from the Charleston Area Medical Center (CAMC) between 1990 and 1991. Only histologically documented adenocarcinomas of the breast were included. Tumor size was characterized using the TNM system and staged according to AJCC criteria. For comparative purposes, details from the two regional centers were compared with tumor characteristics from a large longitudinal cohort of 2,484 breast cancers from the Women's Health Initiative (WHI) study. Baseline median age at diagnosis of women screened at WVUH was younger than patients at CAMC (52 vs. 60). Women diagnosed with triple-negative breast cancer at WVUH and CAMC had similar age distributions. Within the triple-negative patients at WVUH, 44% of patients were less than 50 years of age and 20% were less than 40 years of age. At CAMC, 35% were less than 50 years of age and 7% were less than 40 years of age. For women at WVUH, 61.5% presented with T1 tumors compared to 65.5% at CAMC. These figures were lower than the WHI average of 80.3%. In contrast, more women presented with larger T2 tumors at our medical centers compared with the national study, 32.6% versus 17.4% respectively. At WVUH, 2.3% of women had T3 tumors (> or =5 cm) compared with 1% at CAMC. Similar to the WHI study, 35-42% of women at WVUH and CAMC were diagnosed at the T1c stage. Approximately, 30% were diagnosed with positive lymph nodes, compared to 23% in the national study. Combined breast cancer data from our medical centers show an increase in more advanced tumors and positive regional lymph node involvement at the time of diagnosis compared to national reports. Other factors such as obesity, diabetes, poverty and access to mammography screening could be influencing the poorer outcomes for women with breast cancer in West Virginia.