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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042424-02
Application #
3183721
Study Section
Reproductive Biology Study Section (REB)
Project Start
1987-04-15
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
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Cos, S; Blask, D E (1994) Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. J Pineal Res 17:25-32
Wilson, S T; Blask, D E; Lemus-Wilson, A M (1992) Melatonin augments the sensitivity of MCF-7 human breast cancer cells to tamoxifen in vitro. J Clin Endocrinol Metab 75:669-70
Blask, D E; Lemus-Wilson, A M; Wilson, S T (1992) Breast cancer: a model system for studying the neuroendocrine role of pineal melatonin in oncology. Biochem Soc Trans 20:309-11
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Cos, S; Blask, D E; Lemus-Wilson, A et al. (1991) Effects of melatonin on the cell cycle kinetics and ""estrogen-rescue"" of MCF-7 human breast cancer cells in culture. J Pineal Res 10:36-42
Blask, D E; Pelletier, D B; Hill, S M et al. (1991) Pineal melatonin inhibition of tumor promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: potential involvement of antiestrogenic mechanisms in vivo. J Cancer Res Clin Oncol 117:526-32
Cos, S; Blask, D E (1990) Effects of the pineal hormone melatonin on the anchorage-independent growth of human breast cancer cells (MCF-7) in a clonogenic culture system. Cancer Lett 50:115-9
Hill, S M; Blask, D E (1988) Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 48:6121-6