Carcinogenicity of Estrogens

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DESCRIPTION (provided by applicant): Estrogens have long been associated with breast cancer, because numerous risk factors for the disease relate to a woman's lifelong exposure to endogenous and exogenous estrogen. While prevailing theories for the role of estrogen in carcinogenesis in the mammary gland have been focused on the stimulation of breast-cell proliferation by estrogen, there is also evidence that reactive metabolites produced by cytochrome P450 (CYP)-catalyzed metabolism of exogenous compounds and endogenous estrogens are involved in mutagenesis and breast cancer initiation. The aryl hydrocarbon receptor (AhR) controls the expression of CYP1A1 and CYP1B1, enzymes that are known to catalyze the metabolism of numerous procarcinogens to ultimate carcinogens and estrogens to catechol estrogens. Our studies will focus on a potentially novel role of estrogen in breast cancer: the regulation of Ah responsiveness and expression of the enzymes that metabolically activate procarcinogens in the mammary epithelium. Our broad, long-term goal is to elucidate the mechanisms responsible for estrogen-induced carcinogenesis in the human breast. We present the novel hypothesis that a significant role of estrogens in breast carcinogenesis is the up- regulation of AhR expression, leading to elevated expression and inducibility of the carcinogen-bioactivating enzymes, CYP1A1 and CYP1B1, and a greater propensity for mutations and the initiation of carcinogenesis. Our Specific Aims are to: 1) Determine the mechanism of short-term estrogen regulation of AhR and CYP1B1 expression in breast epithelial and breast tumor cells; 2) Identify the molecular changes responsible for the loss of Ah responsiveness in breast tumor cells due to long-term estrogen deprivation; 3) Evaluate the oncogenic potential of long-term estrogen exposure in human breast epithelial cells. Non- transformed MCF-10A human breast epithelial cells will be exposed long-term to varying concentrations of E2, and indices of cellular transformation will be assessed. We will also determine whether overexpression of CYP1B1 and AhR increases the rates of transformation of breast epithelial cells in vitro and tumorigenicity in vivo. These studies will further our understanding of the regulation of CYP expression that may be important during critical times of development and at times critical for breast cancer initiation and progression. These studies may elucidate roles of estrogen in the regulation of Ah responsiveness, CYP1 expression, and carcinogen bioactivation that may lead to novel breast cancer chemoprevention strategies.