Breast cancer represents 32 percent of all cancers in women. Yet, Oriental women consuming a traditional diet high in soy products have a lower incidence of breast cancer. We have demonstrated that genistein, a component of soy, when injected in prepubertal female rats suppressed the development of chemically-induced mammary cancer. Prepubertal genistein treatment enhanced mammary gland differentiation and resulted in a lower rate of cell proliferation. Now, we propose to investigate dietary genistein exposure for mammary cancer prevention (dose response studies). We will determine the doses to use from studies on gland differentiation, using mammary whole mounts, and cell proliferation, using bromodeoxyuridine immunohistochemistry (IHC). We hypothesize that early exposure to genistein alters gene and protein expression of specific steroid and growth factor pathways to result in maturational effects that render the glands/cells more differentiated and less susceptible for cancer. To investigate mechanisms of action, we propose to measure protein expression (by IHC and western blot) of the estrogen-, progesterone-, and EGF-receptors, and TGF-alpha, EGF, and TCF beta, all modulated by estrogen. We will also investigate the potential of genistein in the diet to alter the reproductive/endocrine system of these animals. This application is a competing continuation of one of two R01 applications submitted as interactive proposals. The title of the IRPG application is """"""""Genistein: Bioavailability, Mechanisms, Cancer Prevention"""""""". The overall goals of our interactive research proposals are to investigate the potential of genistein, a component of soy, to protect against mammary cancer, and to determine the pharmacokinetics and mechanisms of action of genistein in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061742-07
Application #
6172447
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Ross, Sharon A
Project Start
1994-02-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
7
Fiscal Year
2000
Total Cost
$200,304
Indirect Cost
Name
University of Alabama Birmingham
Department
Pharmacology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Jenkins, Sarah; Betancourt, Angela M; Wang, Jun et al. (2012) Endocrine-active chemicals in mammary cancer causation and prevention. J Steroid Biochem Mol Biol 129:191-200
Whitsett Jr, Timothy G; Lamartiniere, Coral A (2006) Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat. Expert Rev Anticancer Ther 6:1699-706
Cotroneo, Michelle S; Wang, Jun; Fritz, Wayne A et al. (2002) Genistein action in the prepubertal mammary gland in a chemoprevention model. Carcinogenesis 23:1467-74
Lamartiniere, Coral A (2002) Timing of exposure and mammary cancer risk. J Mammary Gland Biol Neoplasia 7:67-76
Lamartiniere, Coral A; Cotroneo, Michelle S; Fritz, Wayne A et al. (2002) Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr 132:552S-558S
Fritz, Wayne A; Wang, Jun; Eltoum, Isam Eldin et al. (2002) Dietary genistein down-regulates androgen and estrogen receptor expression in the rat prostate. Mol Cell Endocrinol 186:89-99
Lamartiniere, Coral A; Wang, Jun; Smith-Johnson, Michelle et al. (2002) Daidzein: bioavailability, potential for reproductive toxicity, and breast cancer chemoprevention in female rats. Toxicol Sci 65:228-38
Cotroneo, M S; Wang, J; Eltoum, I A et al. (2001) Sex steroid receptor regulation by genistein in the prepubertal rat uterus. Mol Cell Endocrinol 173:135-45
Cotroneo, M S; Lamartiniere, C A (2001) Pharmacologic, but not dietary, genistein supports endometriosis in a rat model. Toxicol Sci 61:68-75
Brown, N M; Lamartiniere, C A (2000) Genistein regulation of transforming growth factor-alpha, epidermal growth factor (EGF), and EGF receptor expression in the rat uterus and vagina. Cell Growth Differ 11:255-60

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