Breast cancer is the most common cancer among U.S. females and is the second leading cause of death among women. In the last decade, the incidence of breast cancer has increased at a rate of approximately 2% per year. There is speculation that environmental chemicals, especially ecoestrogens, may be responsible for some of these cancers. We have hypothesized that estrogenically-active chemicals can exert predisposition for or against breast cancer, depending on the xenobiotic and timing of exposure. We have recently demonstrated that diethylstilbestrol and genistein given neonatally alter cell differentiation and cell proliferation in mammaries of 50 day old female rats and that these two estrogenically-active xenobiotics increased the Latency and decreased the incidences and multiplicities of dimethylbenz(a)anthracene (DMBA)-induced mammary tumors (22,23). This is to be contrasted to prenatal diethylstilbestrol exposure increasing tumor multiplicity in the mammaries of rats exposed to DMBA (29). These data support the theory of developmental windows and estrogenically-active xenobiotics playing a role in predisposition for mammary cancer. It is our objective to investigate the potential of six environmental chemicals during three critical periods of development for altering susceptibility for breast cancer and to investigate two mechanisms that could be predictive indicators of this disease. Sprague Dawley CD rats will be exposed during the prenatal, neonatal and pubertal periods of development to diethylstilbestrol, genistein, l-(o-chlorophenyl)-l-l)p- chlorophenyl)-2,2,2-trichloroethane (o,p'-DDT), Aroclor 1221, Aroclor 1254 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We will subsequently study cell differentiation in mammary whole mounts and measure cell proliferation using proliferating cell nuclear antigen as a marker of mitotic activity. The maturation of undifferentiated terminal end buds to more differentiated lobules have been shown to yield structures that are less susceptible to DNA damage and replication (2). Likewise, cells that have a higher proliferation index are more susceptible to carcinogens. We will also investigate the effects of these environmental chemicals on pituitary, ovarian and uterine weights as markers of estrogen action and on circulating levels of estrogen, progesterone, prolactin and growth hormone. Finally, we will investigate the potential of selected xenobiotics and developmental windows to alter latency, incidence and multiplicity of DMBA induced adenocarcinomas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES007273-01
Application #
2156574
Study Section
Special Emphasis Panel (SRC)
Project Start
1994-09-30
Project End
1997-09-29
Budget Start
1994-09-30
Budget End
1995-09-29
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Lamartiniere, Coral A (2002) Timing of exposure and mammary cancer risk. J Mammary Gland Biol Neoplasia 7:67-76
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; Lamartiniere, C A (2001) Pharmacologic, but not dietary, genistein supports endometriosis in a rat model. Toxicol Sci 61:68-75
Lamartiniere, C A; Murrill, W B; Manzolillo, P A et al. (1998) Genistein alters the ontogeny of mammary gland development and protects against chemically-induced mammary cancer in rats. Proc Soc Exp Biol Med 217:358-64
Lamartiniere, C A; Zhang, J X; Cotroneo, M S (1998) Genistein studies in rats: potential for breast cancer prevention and reproductive and developmental toxicity. Am J Clin Nutr 68:1400S-1405S
Brown, N M; Wang, J; Cotroneo, M S et al. (1998) Prepubertal genistein treatment modulates TGF-alpha, EGF and EGF-receptor mRNAs and proteins in the rat mammary gland. Mol Cell Endocrinol 144:149-65
Brown, N M; Manzolillo, P A; Zhang, J X et al. (1998) Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis 19:1623-9
Dalu, A; Haskell, J F; Coward, L et al. (1998) Genistein, a component of soy, inhibits the expression of the EGF and ErbB2/Neu receptors in the rat dorsolateral prostate. Prostate 37:36-43
Fritz, W A; Coward, L; Wang, J et al. (1998) Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 19:2151-8
Murrill, W B; Brown, N M; Zhang, J X et al. (1996) Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis 17:1451-7

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