Β-Blockers and Cancer: the impact of stress on cancer
Jacob Schor, ND, FABNO
August 22, 2013
Several studies have given us a greater understanding of how stress encourages cancer progression. A study by Botteri et al published August 3, 2013 in the journal Breast Cancer Research and Treatment suggests that taking Β-blockers may have a beneficial effect in women with triple negative breast cancer. While these results in themselves are of great interest, especially to women with triple negative breast cancer, they have greater significance. They add weight to a theory proposed last January by Guillermo et al in Nature Communications on the role of stress in cancer.
The purpose of this review is not to convince you that cancer patients suffer from a β-blocker deficiency and must take these drugs. Rather it is to help further our understanding of the role stress plays in cancer.
Let’s hold off on Botteri’s report for a moment and start with Guillermo’s paper that appeared in the January 29th edition of Nature Communications. It is a bit complicated as it summarizes multiple studies. Earlier work had established that activation of β-adrenergic receptors on ovarian cancer cells turned on pro-survival pathways , , . That is stress hormones attach directly to ovarian cancer cells and make them harder to kill. Botteri’s group examined stress and the risk of ovarian cancer progression via the activation of the Src pathway. For years both patients and forward thinking doctors have believed there is a link between stress and cancer progression but little evidence supported this feeling; certainly no clear mechanism of action had been identified. The Src pathway provides the biochemical explanation of how stress acts to push cancer’s advance.
“Src is a non-receptor protein tyrosine kinase that transduces signals that are involved in the control of a variety of cellular processes such as proliferation, differentiation, motility, and adhesion. Src is normally maintained in an inactive state, but can be activated transiently during cellular events such as mitosis, or constitutively by abnormal events such as mutation ….. Activation of Src occurs as a result of disruption of the negative regulatory processes that normally suppress Src activity, and understanding the various mechanisms behind Src activation has been a target of intense study.” In other words, this Src pathway when activated regulates many of the processes that allow cancer to grow. For cancer researchers, understanding this protein is high on their wish lists.
The first phase of Guillermo’s study found that treating ovarian cancer cells in-vitro with noradrenaline increased production of the proteins that encourage tumor cell growth. Ovarian cancer cells do not produce noradrenaline but they do have receptors that noradrenaline binds to. Exposing these cancer cells to amounts of noradrenaline similar to those found in ovarian tissues both under normal and stressed conditions showed that the noradrenaline levels during stress activated Src pathways that in turn caused a cascade of kinase pathways being activated including KIT, EGFR, ABL1, and IGF-1. Src activation increased tumor cell invasiveness, migration and proliferation.
This connection between stress, Src activation and tumor progression was confirmed by using tumor-implanted mice. Stressing tumor-implanted mice was enough to activate Src.
Next, Guillermo’s team demonstrated this connection between stress, Src activation, and ovarian cancer survival in humans. They looked at tumor tissue samples from 91 patients with invasive epithelial ovarian cancer and found a correlation between scores of psychological depression in the patients with Src activation in the tumors. Src levels were high in 88% of the 91 human ovarian tumor samples and these elevations were associated with worse outcomes, as measured by shorter survival times. The more emotionally depressed the patients were as measured by psychological surveys, the higher their Src scores.
The authors took this research one step further. They already knew that β -blocker use would block stress activation of the Src pathway so they compared use of β -blockers and the risk of death from cancer. Data was already available from the FDA’s Adverse Event Reporting System that could be analyzed. In people using β-blockers, risk of death from any type of cancer was reduced by an average of 17% and risk of dying of ovarian or cervical cancer was reduced by almost 15%.
Thus Guillermo and colleagues’ paper suggested a clear mechanism as to how stress helps cancer cells grow. Because this theory also suggests a benefit from using β-blockers, their work triggered a flurry of studies in the last half year looking at β-blockers and cancer.
Botteri’s paper is the most recent as of this writing. Botteri’s group looked for possible therapeutic effect of β-blockers in triple-negative breast cancer (TNBC) patients. Triple negative breast cancer refers to cancer cells that test negative for estrogen and progesterone receptors (double-negative) and also do not over-express the Her-2-neu protein. These cancer types are relatively resistant to current forms of treatment.
Botteri’s colleagues identified 800 postmenopausal women treated between 1997 and 2008 for early TNBC. About 9% of these women were taking β-blockers at the time of diagnosis. Over the five years after diagnosis, nearly 28% of the women not taking β-blockers had their cancer recur or progress while less than 14% of the women taking β-blocker did. In simple words taking β-blockers seems to have reduced the risk of recurrence by half.
When the statisticians were done with the data, adjusting for all the other factors that might have influenced these patients’ outcomes, the results were even better. Using β-blockers reduced risk of metastasis by 68% and risk of dying by 58%. [Adjusted HRs for metastases and for BC deaths were 0.32 (95 % CI 0.12-0.90) and 0.42 (95 % CI 0.18-0.97)]
The path of scientific research is rarely a straight line and while this study produced significant associations between this particular subset of breast cancers, not all data have been consistent.
Danish researchers reported in June that they could not find a benefit in using β-blockers or other blood pressure reducing drugs in breast cancer. Sørensen et al analyzed data from 18,733 women diagnosed with non-metastatic breast cancer and compared their 10-year-recurrence rate with the use of β-blockers, Ace inhibitors, and angiotensin receptor blockers. In the raw data, use of any β-blocker was associated with a 9% reduction in recurrence but when the data was analyzed taking into account other risk factors, β-blocker use actually appeared to increase risk by about 30% (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0 and adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Two particular β-blocking drugs, metoprolol and sotalol actually seemed to increase recurrence rates by 50% and 100% respectively (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0).
So do we believe the Italian or the Danish data? Or can they both be true?
Perhaps we haven’t been asking the right questions in these studies. In an August 7th discussion of this Nagaraja et al from MD Anderson point out that, “… all published studies so far are retrospective and most do not take into account the specific β-blocker used or address which is most likely to benefit cancer patients. The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors.
Thus perhaps only specific β-blocker drugs will provide benefit in tumors that express the right β-receptors. Or it may simply be that β-blocker impact is easier to see in the ‘nastier’ cancers, that is in cancers with a worse prognosis and a more rapid progression.
Few of us are interested in prescribing β-blockers to our cancer patients. What is important about these studies is that they affirm our intuitive belief that stress reduction will aid cancer patients. These studies also give us a rough estimate of how much impact stress reduction might have.
Now that the Src pathway has been identified as a potential target, we see papers that evaluate natural substances and drugs as to their cancer and their Src inhibitory effects. Recent reports range from telling us that naja naja snake venom blocks breast cancer cell migration by preventing Src activation to discussing a plant flavonoid called isorhamnetin derived from a Mexican psychedelic plant and its possible role in treating colorectal cancer.
We may soon be able to say that active stress reduction may have clearly measurable therapeutic benefit in cancer.
Yet at this point we cannot say this; there isn’t enough data. There are certainly short-term studies suggesting that particular interventions will reduce stress levels or improve quality of life. For example, a study is underway in Japan treating patients with gynecologic cancers with massage. Yet with only 8 massage sessions over a two-month period it is unlikely that this study will generate the needed data on survival.
A Danish study from April 2013 reported on 336 women who were randomized after breast cancer surgery and half were trained in the mindfulness-based stress reduction program (MBSR) for 8 weeks. At the end of 12 months, the “intervention had clinically meaningful, statistically significant effects on depression and anxiety.” The unasked question though was did it change Src activation or more important change survival.
A 2010 study informs us that in a group of 162 breast cancer patients practicing QiGong several hours a week for ten weeks was associated with improved quality of life, less fatigue and lower c-reactive protein levels.
A 2009 paper reported that practicing Transcendental Meditation™ improved various quality of life scores in 230 women diagnosed with breast cancer. Again, they are not answering the questions we are interested in.
In the future measuring Src activity may have both a prognostic value and serve as a measure of benefit from stress reducing interventions. Yet not at this point in time. There is little published information on stress reduction and Src activation, only the assumption that it will help. Nor is this writer aware of human research on exercise and Src activation.
There is a kind of Catch-22 with stress and cancer. Once someone has cancer, stress levels rise. Few patients will ever report that stress decreased post diagnosis.
Among a host of practical day-to-day worries, cancer survivors are plagued with the fear that their cancer will return. Not surprisingly, fear of cancer recurrence is common in survivors and is a major contributor to psychological stress. An August 2013 paper that followed 1,281 cancer patients assessing them at diagnosis and a year after treatment was completed. Those with moderate to high fear of their cancer returning changed little over time: from 84.7% initially to 84.8% twelve months after rehabilitation was completed.
Cancer in this way can become self-perpetuating process in that the diagnosis itself raises stress levels, which in turn increase risk of recurrence or progression. Breaking the cycle by decreasing stress’ effect on the physiology are not about just feeling more comfortable and improving perceived quality of life, decreasing stress is about treating cancer. Seeking workable interventions to lower stress is important and may have lasting effects of the same magnitude as those prescribed by medical oncology.
Guillermo A-P, Allen J, Cruz A, Stone R, et al. Src activation by b-adrenoreceptors is a key switch for tumour metastasis. Nature Communications. 29 Jan 2013;4:1403.
Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 2006;12, 939–944.
Sood, A. K. et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J. Clin. Invest. 2010;120:1515–1523.
Sood, A. K. et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin. Cancer Res. 2006;12:369–375.
Jeffrey D Bjorge, Andrew Jakymiw and Donald J Fujita. Selected glimpses into the activation and function of Src kinase. Oncogene 20 November 2000, Volume 19, Number 49, Pages 5620-5635
Sørensen GV, Ganz PA, Cole SW, Pedersen LA, Sørensen HT, Cronin-Fenton DP, Garne JP, et al. Use of β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and risk of breast cancer recurrence: a Danish nationwide prospective cohort study. J Clin Oncol. 2013 Jun 20;31(18):2265-72. doi: 10.1200/JCO.2012.43.9190. Epub 2013 May 6.
Nagaraja AS, Sadaoui NC, Lutgendorf SK, Ramondetta LM, Sood AK. β-blockers: a new role in cancer chemotherapy? Expert Opin Investig Drugs. 2013 Aug 7. [Epub ahead of print]
Wheeler DL, Iida M, Dunn EF.The role of Src in solid tumors. Oncologist. 2009 Jul;14(7):667-78. doi: 10.1634/theoncologist.2009-0009. Epub 2009 Jul 6.
Tsai PC, Chu CL, Chiu CC, Chang LS, Lin SR. Inhibition of Src activation with cardiotoxin III blocks migration and invasion of MDA-MB-231 cells. Toxicon. 2013 Aug 7. pii: S0041-0101(13)00270-5. doi: 10.1016/j.toxicon.2013.07.021.
Saud SM, Young MR, Jones-Hall YL, Ileva L, Evbuomwan MO, Wise J, Colburn NH, et al. Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β-catenin. Cancer Res. 2013 Jul 1.
Donoyama N, Satoh T, Hamano T. Effects of Anma massage therapy (Japanese massage) for gynecological cancer survivors: study protocol for a randomized controlled trial. Trials. 2013 Jul 24;14:233. doi: 10.1186/1745-6215-14-233.
Würtzen H, Dalton SO, Elsass P, Sumbundu AD, Steding-Jensen M, Karlsen RV, Andersen KK, et al. Mindfulness significantly reduces self-reported levels of anxiety and depression: results of a randomised controlled trial among 336 Danish women treated for stage I-III breast cancer. Eur J Cancer. 2013 Apr;49(6):1365-73.
Oh B, Butow P, Mullan B, et al. Impact of medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: a randomized controlled trial. Ann Oncol. 2010;21:608-614.
Nidich SI, Fields JZ, Rainforth MV, Pomerantz R, Cella D, Kristeller J, Salerno JW, Schneider RH. A randomized controlled trial of the effects of transcendental meditation on quality of life in older breast cancer patients. Integr Cancer Ther. 2009 Sep;8(3):228-34. doi: 10.1177/1534735409343000.
Corter AL, Findlay M, Broom R, Porter D, Petrie KJ. Beliefs about medicine and illness are associated with fear of cancer recurrence in women taking adjuvant endocrine therapy for breast cancer. Br J Health Psychol. 2013 Feb;18(1):168-81. doi: 10.1111/bjhp.12003. Epub 2012 Nov 8.
Roland KB, Rodriguez JL, Patterson JR, Trivers KF. A literature review of the social and psychological needs of ovarian cancer survivors. Psychooncology. 2013 Jun 13. doi: 10.1002/pon.3322. [Epub ahead of print]
Mehnert A, Koch U, Sundermann C, Dinkel A. Predictors of fear of recurrence in patients one year after cancer rehabilitation: A prospective study. Acta Oncol. 2013 Aug;52(6):1102-9. doi: 10.3109/0284186X.2013.765063. Epub 2013 Feb 5.