Carcinogenicity of Estrogens

说明(申请人提供)：雌激素长期以来一直与乳腺癌有关，因为这种疾病的许多危险因素与女性终身接触内源性和外源性雌激素有关。虽然雌激素在乳腺癌变中的作用的主流理论主要集中在雌激素对乳腺细胞增殖的刺激作用，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了突变和乳腺癌的启动。芳香烃受体(AhR)控制细胞色素P1A1和细胞色素P1B1的表达，这两种酶可催化多种致癌物代谢为最终致癌物，将雌激素代谢为邻苯二酚类雌激素。我们的研究将集中在雌激素在乳腺癌中的一个潜在的新作用：调节AH的反应性和代谢激活乳腺上皮中前致癌物的酶的表达。我们广泛的、长期的目标是阐明雌激素诱导人类乳房癌变的机制。我们提出了一个新的假设，即雌激素在乳腺癌发生中的重要作用是上调AhR的表达，导致致癌生物激活酶CYP1A1和CYP1B1的表达和诱导性增加，并有更大的突变倾向和致癌启动。我们的具体目标是：1)确定雌激素短期调节乳腺上皮和乳腺肿瘤细胞AhR和CYP1B1表达的机制；2)确定长期雌激素剥夺导致乳腺肿瘤细胞AhR和CYP1B1反应性丧失的分子变化；3)评估长期雌激素暴露在人类乳腺上皮细胞中的致癌潜力。未转化的MCF-10A人乳腺上皮细胞将长期暴露于不同浓度的E2，并将评估细胞转化指数。我们还将确定过度表达CYP1B1和AhR是否会增加乳腺上皮细胞在体外的转化率和体内的致瘤性。这些研究将进一步加深我们对CYP表达调控的理解，它在发育的关键时期可能是重要的，有时对乳腺癌的发生和发展也是至关重要的。这些研究可能阐明雌激素在AH反应性、CYP1表达和致癌物生物激活中的调节作用，这些作用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.