Carcinogenicity of Estrogens

描述（由申请人提供）：雌激素长期以来与乳腺癌有关，因为该疾病的许多风险因素与女性终身暴露于内源性和外源性雌激素有关。虽然关于雌激素在乳腺癌发生中的作用的流行理论一直集中在雌激素刺激乳腺细胞增殖上，但也有证据表明，细胞色素P450（CYP）催化的外源性化合物和内源性雌激素代谢产生的反应性代谢产物参与诱变和乳腺癌的发生。芳香烃受体（AhR）控制CYP 1A 1和CYP 1B 1的表达，已知这些酶催化许多原致癌物代谢为最终致癌物，并催化雌激素代谢为儿茶酚雌激素。我们的研究将集中在一个潜在的新的作用，雌激素在乳腺癌中：调节Ah的反应性和表达的酶，代谢激活乳腺上皮中的原癌原。我们广泛的长期目标是阐明雌激素诱导的人类乳腺癌发生的机制。我们提出了一个新的假说，即雌激素在乳腺癌发生中的重要作用是上调AhR表达，导致致癌物生物活化酶CYP 1A 1和CYP 1B 1的表达升高和诱导，以及更大的突变倾向和致癌作用的启动。我们的具体目标是：1）确定乳腺上皮细胞和乳腺肿瘤细胞中AhR和CYP 1B 1表达的短期雌激素调节机制; 2）确定由于长期雌激素剥夺导致乳腺肿瘤细胞中Ah反应性丧失的分子变化; 3）评估人类乳腺上皮细胞中长期雌激素暴露的致癌潜力。将非转化的MCF-10A人乳腺上皮细胞长期暴露于不同浓度的E2，并评估细胞转化指数。我们还将确定是否CYP 1B 1和AhR的过度表达增加乳腺上皮细胞在体外和体内致瘤性的转化率。这些研究将进一步我们的理解的调节，可能是重要的，在关键时期的发展和乳腺癌的发生和发展的关键时期。这些研究可能阐明雌激素在调节Ah反应性、CYP 1表达和致癌物生物活化中的作用，从而可能导致新的乳腺癌化学预防策略。

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.