Breast cancer is one of the leading causes of human cancer. Chemically- induced mammary cancer in rats provides a model of susceptibility for the study of carcinogenesis in human mammary glands. Chemoprevention rather than cancer treatment is a preferred means of health promotion. Our goal is to identify an efficacious chemopreventive agent for human females inherently susceptible for mammary cancer. In this interactive R0l we propose to investigate a novel approach, chemoprevention via critical period(s) of development with a nutritional component of soy-based foods, i.e., genistein. Genistein is a phytoestrogen found in soy-based products, the latter having been associated with a 2 to 5-fold lower incidence of and death from breast cancer in women consuming soy products not only as adults, but also pre- and postnatally. Estrogens given either neonatally or just prior to carcinogen exposure have been shown to prevent mammary adenocarcinomas. Since genistein is a weak estrogen agonist/antagonist, we hypothesize that it will exert a chemopreventive effect via imprinting mechanisms and/or developmental maturation of the mammary when given neonatally. Our experiments will l) determine if biochemical imprinting during the neonatal period, or prepubertal exposure to genistein will reduce the incidence of dimethylbenz(a)anthracene- induced mammary adenocarcinomas, 2) if neonatal and prepubertal exposure to genistein will alter mammary cell differentiation (using mammary whole mounts) and proliferation (using PCNA/cyclin immunohistochemistry), and 3) if early genistein exposure will alter activation/detoxication mechanisms in the mammary. The latter will be assessed by measuring the rate of formation and persistence of carcinogen-DNA adducts as a means of determining the programming effect of genistein On initiation mechanisms of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA061742-01
Application #
2102504
Study Section
Special Emphasis Panel (SRC (70))
Project Start
1994-02-01
Project End
1997-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
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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