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    Research Grants Awarded

    The Effect of Melatonin's Efficacy at Reducing Primary and Metastatic Breast Cancer Risk

    Study Section:
    Psycho-Social and Complementary Treatment

    Scientific Abstract:
    Melatonin is believed to have many beneficial effects on general health, including anticancer, antimetastatic, and estrogen inhibiting actions. However, during aging, melatonin levels decrease. Melatonin levels are further reduced in women taking hormone replacement therapy (HRT). We postulate that the reduced levels of melatonin may, in part, contribute to the increase in breast cancer risk associated with HRT. Thus, using a preclinical model of HER2 + breast cancer, our first aim will investigate whether supplementing melatonin levels in the presence and absence of HRT will reduce the risk of primary and metastatic mammary cancer. To conform with current HRT recommendations, low dose HRT will be tested in cycling mice to mimic peri- vs. postmenopausal women. Mammary tumor latency, incidence, growth, metastatic incidence, and expression of metastatic markers will be investigated in four treatment groups of MMTV- neu females (expressing the neu protooncogene): control, melatonin, HRT, and melatonin + HRT. Potential mechanisms of melatonin protection will also be examined in the normal mammary gland. For our second aim, we will investigate whether the estrogen-inhibiting and progesterone-receptor-stimulating actions reported for melatonin in the uterus will allow a lower dose of progestin to be used in HRT for uterine protection. Markers of proliferation and hormone responsiveness will be examined in the uterus to determine the effects of the hormone treatments with and without melatonin supplementation. Since progestins are implicated in the elevated risk of both primary and metastatic breast cancer, the ability to use less progestin to provide uterine protection, in addition to melatonin’s anticancer actions, suggests that both risks would be reduced. We expect to demonstrate that melatonin used alone and in conjunction with low dose HRT can reduce 1) the risk of developing mammary tumors and lung metastases, 2) the levels of metastatic markers in the mammary tumors, and 3) the expression of hormone responsive markers in the normal mammary gland and uterus. These results would suggest that restoring the declining levels of melatonin in aging women would allow them to use HRT as needed during perimenopausal years to alleviate menopausal symptoms without increasing breast cancer risk. In addition, melatonin would provide other health benefits to perimenopausal women that affect quality of life and survival.

    Lay Abstract:
    Melatonin is a hormone produced in the body during the dark hours of each day. For this reason, it has been associated with improved sleep; but melatonin has many other beneficial actions, such as its anticancer and estrogen inhibiting properties. However, melatonin levels decrease with age. Conversely, breast cancer risk increases with age, perhaps due, in part, to the declining nighttime production of melatonin. The levels of melatonin are further decreased in women taking hormone replacement therapy (HRT). Therefore, we hypothesize that the reduced levels of melatonin in menopausal women may be partially responsible for the increased breast cancer risk associated with HRT, and this increased risk could be reduced or eliminated by supplementing HRT with melatonin therapy to restore these inadequate levels. Therefore, in this study, we will examine whether melatonin can prevent the increased risk of breast cancer development using a mouse model that mimics HER2 + breast cancer. Four groups (control, melatonin, HRT, and melatonin + HRT) will be examined for the age which tumors occur and for tumor incidence, growth, and metastasis (ability to spread). This study is designed to test current recommendations for HRT, by testing low dose therapy and treating during a period to mimic perimenopausal (when menopausal symptoms are disruptive and cycling still occurs) vs. postmenopausal women. Thus, melatonin would be given, at the minimum, during short-term HRT use as needed to control menopausal symptoms. We expect melatonin, both alone and combined with HRT, to cause 1) fewer females to develop tumors, 2) tumors to be found at later ages, and 3) fewer tumors to spread to the lungs compared to untreated and HRT-treated groups. Melatonin is a well-tolerated, over-the-counter supplement with few side effects. Besides its potential to reduce the risk of developing breast cancer and its spread to other organs, melatonin also has many other beneficial effects that can improve quality of life for women during the transition to menopause, including reducing the risk of other diseases, such as heart disease, Alzheimer’s disease, osteoporosis and other cancers, as well as improving mood, memory, and sleep patterns. Therefore, the addition of this alternative therapy to HRT could not only reduce the risk of breast cancer development, but improve a woman’s general health and well-being by restoring her diminishing levels of this natural hormone.