MECHANISMS OF ENVIRONMENTAL AGENTS INDUCED BREAST CANCER

本研究的长期目标是：(L)改造正常人 乳腺上皮细胞(HBEC)体外分化为不同阶段 化学-物理致癌物和化学-物理致癌物和 癌基因；2)确定一种类型的HBEC(I型)是否与干细胞和 腔上皮细胞特性是肿瘤的靶细胞 各种致癌物质的转化；3)确定在哪一种 在肿瘤转化阶段，不同已知的乳腺癌致癌物质是 最有效地发挥它们的作用；以及4)阐明 以及乳腺癌发生的分子机制。为了达到这些目的，使用两个 最著名的影响乳腺癌发生的因素(即电离 辐射和类雌激素化合物)，我们建议1)确定电离 辐射是肿瘤的有力启动者、促进者或进展者。 正常HBEC的转化(延长寿命、永生、虚弱 致瘤性，以高致瘤性为终点)；2)发展 正常和癌前病变HBEC表达雌激素受体(ER)和 对雌激素刺激细胞增殖作出反应；3)测试是否及如何 雌激素类化合物对雌激素受体阳性正常人肿瘤转化的影响 和癌前病变HBEC；4)生物学和分子特征 电离诱发癌前和癌变HBEC的性质 辐射/雌激素揭示乳腺的遗传和分子机制 致癌。为了实现这些特定的目标，一种新的栽培技术 为了培养两种类型的正常HBEC，已经开发出了分子和 分子比较基因组杂交等技术 细胞遗传学分析和Northern、Western印迹分析、RT-PCR、DNA 将使用测序、免疫染色、激光细胞术来确定 多种癌基因、抑癌基因在癌前病变中的表达 和处于不同阶段的肿瘤细胞。除了有可能 阐明乳腺癌发生、发展的机制 系统将有助于识别环境致癌物和在 开发潜在的乳房X光照相和辐射防护剂 乳腺癌的化学预防/治疗策略(例如 靶向正常或癌前病变的分化)。

The long-term objectives of this study are l) to transform normal human breast epithelial cells (HBEC) in vitro stepwise to various stages of preneoplastic and malignant cells by chemical\physical carcinogens and oncogenes; 2) to determine if one type of HBEC (Type I) with stem cell and luminal epithelial cell characteristics is the target cell for neoplastic transformation by various breast carcinogens; 3) to determine at which stage of neoplastic transformation, different known breast carcinogens are most effective in exerting their effects; and 4) to elucidate the genetic and molecular mechanisms of breast carcinogenesis. To these ends, using two best known agents that affect breast carcinogenesis (i.e. ionizing radiation and estrogenic compound), we propose 1) to determine if ionizing radiation is a potent initiator, promotor or progressor for neoplastic transformation of normal HBEC (with extended lifespan, immortality, weak tumorigenicity, and high tumorigenicity as end points); 2) to develop normal and preneoplastic HBEC that express estrogen receptor (ER) and respond to estrogens for cell proliferation; 3) to test if and how estrogenic compounds affect neoplastic transformation of ER-positive normal and preneoplastic HBEC; and 4) to characterize the biological and molecular nature of preneoplastic and neoplastic HBEC induced by ionizing radiation/estrogen to reveal the genetic and molecular mechanisms of breast carcinogenesis. To accomplish these specific aims, a new culture technique to grow two types of normal HBEC has been developed and molecular techniques, such as comparative genomic hybridization for molecular cytogenetic analysis and Northern, Western blot analysis, RT-PCR, DNA sequencing, immunostaining, laser cytometry will be used to determine the expression of various oncogene, tumor suppressor genes for preneoplastic and neoplastic cells at different stages. Besides the potential to elucidate the mechanism of breast carcinogenesis, the development of this system will be instrumental in identifying environmental carcinogens and in developing potential radiation protectors for mammography and chemopreventive/therapeutic strategies for breast cancer (e.g. differentiation of target normal or preneoplastic HBEC).