Melatonin, Estrogen and Breast Cancer
September 27, 2007
Melatonin inhibits breast cancer via a number of pathways
Melatonin can slow the growth of many types of cancer especially hormone dependent ones. Past newsletters have mentioned its particular role in breast cancer. This newsletter will look at some of the mechanisms by which melatonin acts against breast cancer.
Melatonin is a hormone produced in the brain by the pineal gland. Production is triggered by darkness and stopped by light. A 1978 paper published in the Lancet predicted melatonin's role in breast cancer. This hypothesis was based on knowledge that melatonin decreases some of the hormones that control breast gland development and which stimulate the growth of hormone dependent tumors. Early research demonstrated that women with breast cancer had lower melatonin levels in their blood. Epidemiologic studies demonstrated a much lower incidence of breast cancer in blind women and even an inverse relationship between breast cancer and the degree of visual impairment. The greater the visual impairment, the higher the melatonin level, the lower the estrogen levels and the lower the risk. Working night shifts or being exposed to low frequency electromagnetic radiation both suppress melatonin levels and unsurprisingly, increase breast cancer rates. We have reviewed much of this evidence in the past.
The role of estrogen in breast cancer was first established in 1896 when Beatson demonstrated that removing a woman's ovaries inhibited the growth of breast tumors.
Most of the current advances in treating breast cancer stem from Beatson's experiments.
Research now solidly confirms that estrogens cause and promote breast cancer. There is still debate whether these effects are simply due to estrogen's effect at stimulating breast cell growth or whether estrogen and its metabolites actually are cancer causing agents.
Of course, it is probably a combination of both, but you know how everyone wants one answer to be the right one.
Two-thirds of breast cancers occur in post menopausal women when the ovaries are in retirement and total estrogens are relatively low. The concentration of estradiol in their breast tumors is higher than in the blood or in normal breast tissue. After menopause, estrogens are made from adrenal androgens and converted in the tissue through the aromatase pathway.
Two major pharmacologic approaches to treating breast cancer have been developed based more or less on Beatson's discovery. The first, Selective estrogen receptor modulation (SERM) is typified by the drug tamoxifen. In this approach, the drug binds to the estrogen receptors on breast tissue, preventing estrogen from having an effect. The second approach, Selective estrogen enzyme modulators (SEEMS) are typified by the aromatase inhibitors. Aromatase inhibitors prevent the production of estrogen from the adrenal hormones in post menopausal women, lowering estrogen effect by lowering estrogen production.
There are a number of different ways estrogen may act against breast cancer. The simplest is as an antioxidant. Estrogens are metabolized by cytochrome p450 into various hydroxylated products such as 2-,4- and 16-alpha-hydroxyestradiol. The two and four versions are oxidized into semiquinones which can react with oxygen forming super-oxide anion radicals. Melatonin, because it can act as a free radical scavenger, can prevent damage from these estrogen derived radicals.
Another possibility is that melatonin enhances immune function. High concentrations of estrogen suppress the immune system. Melatonin reduces estrogen level and increases immune function.
Still another possibility is that melatonin has a direct effect on telomerase activity in breast cancer cells.
Though all of these actions are possibilities and to some degree play a role, the main idea explaining melatonin's effect on breast cancer focuses on melatonin's interaction with both the synthesis of estrogen and with the estrogen signaling pathways.
Melatonin can influence estrogen in three general ways. First, it decreases synthesis from the ovaries and decreases the levels circulating in the body and reaching the breast. Second, melatonin interacts with the estrogen receptors on breast tumor cells making them less responsive to estrogen. Third, melatonin decreases the activity of the aromatase enzyme, acting in a manner similar to the aromatase inhibiting drugs.
As tedious as these details sound, they deserve elaboration, even if it is just so I can explain them to myself and perhaps remember them.
In wild animals, melatonin controls seasonal reproductive cycles. Melatonin decreases ovarian estrogen secretion in lots of mammals. If melatonin production is low, it allows ‘unopposed' estrogen secretion. With all our indoor and outdoor lighting, we all suffer from ‘overexposure' that produces chronically low melatonin levels.
Melatonin at concentrations that should be found in the body at night counteracts the estradiol effect at stimulating breast cancer cell growth and tumor invasion. It increases the sensitivity of breast cancer cells to tamoxifen and decreases the expression of proteins that the cancer cell makes that help it grow. In humans, “administration of melatonin together with tamoxifen induced objective tumor regression in metastatic breast cancer in patients refractory to tamoxifen alone.”
Melatonin appears to block estrogen action in a different way than the drug tamoxifen. Melatonin does not bind to the estrogen receptor (ER), nor block estrogen from binding to the ER. Instead, melatonin appears to decrease the number of estrogen receptors on breast tissue cells and prevent the message from getting sent when estrogen does bind to the ER. This melatonin effect occurs when it binds to specific melatonin receptors (MT1) on the breast cells. These MT1 receptors are found on all breast cells but they are much more numerous on breast cancer cells.
More recent research has demonstrated that melatonin at, “…physiologic concentrations reduces aromatase activity…” in breast cancer cells. Recall from that newsletter that I can't remember if I sent out, that, in post menopausal women, the enzyme aromatase converts a hormone made in the adrenal glands into estrogen. Blocking the aromatase enzyme blocks estrogen stimulation of breast cancer.
Melatonin is a hormone with many different actions in the body and that include decreasing circulating levels of estrogen and inhibiting synthesis of estrogen. Melatonin does this through mechanisms that differ from the ones employed by current drugs used to treat breast cancer. Thus it should be no surprise that melatonin in combination with these drugs enhances their action.
For women at high risk of getting breast cancer, it makes sense to maximize melatonin production. For women with breast cancer we routinely supplement with melatonin at bed time.
Past newsletters on melatonin:
Sleepless in Park Hill http://denvernaturopathic.com/sleepless.htm
Sanchez-Barcelo et al. Melatonin - estrogen interactions in breast cancer. J. Pineal Res. 2005;38:217-222
Sanchez-Barcelo et al. Melatonin and mammary cancer: a short review. Endocrine Relatedd Cancer (2003) 10 153-159