The long range goal of this research is to further elucidate and understand the mechanisms by which melatonin (Mel), the major hormone of the pineal gland, inhibits the proliferation of hormone-responsive breast cancer in vivo and in vitro in both animal and human models of breast cancer. The proposed studies will determine the effects of Mel and/or pinealectomy on the development and growth of carcinogen-induced breast cancers in female rats. Studies will address the hypothesis that Mel is inhibitory while pinealectomy is stimulatory to mammary tumorigenesis. Certain experiments will test whether Mel is a more effective inhibitor of breast cancer growth when administered during either the initiation or promotional phases of carcinogenesis. Moreover, these experiments will determine whether there is a diurnal rhythm of responsiveness to the inhibitory effects of Mel in the animal models of human breast cancer. Additional studies will determine whether replacement of the daily Mel signal in pinealectomized rats attenuates the tumor-promoting effects of pinealectomy. Blood levels of estradiol (E2), prolactin (PRL) as well as E2 and PRL receptor binding in tumor tissue will be correlated with the effects of Mel and/or pinealectomy on mammary tumorigenesis. Other studies will test the effects of Mel on the growth of established carcinogen-induced breast cancers in intact and hypophysectomized rats in response to E2 and/or PRL. Other in vitro studies will determine the effects of Mel directly on the growth, hormone binding, estrogen sulfotransferase activity and mitogenic protein synthesis/secretion of carcinogen-induced breast cancer cells as well as estrogen-responsive human breast cancer cells. These experiments will also examine the ultrastructural correlates of the Mel's inhibition of human breast cancer cell growth in vitro. Related studies will determine the effects of Mel on carcinogen-induced and human breast cancer cell growth in response to E2 and/or PRL. This research will increase our understanding of the neuroendocrine, peripheral endocrine and cellular-molecular mechanisms by which Mel inhibits breast cancer growth and may lead to the use of Mel as a new antineoplastic agent in the treatment of hormone-responsive human breast cancer.
