ESTROGEN BIOTRANSFORMATIONS AND BREAST CANCER ETIOLOGY

雌激素生物转化和乳腺癌病因

• 批准号: 2462220
• 负责人: ROBERT W BRUEGGEMEIER
• 金额: $ 22.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-18 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2462220
• 关键词: aromatase; biotransformation; breast neoplasms; connective tissue cells; disease /disorder etiology; enzyme activity; estradiol; estrogen analog; estrogens; gene expression; human tissue; mammary epithelium; matrigel; neoplasm /cancer genetics; oxidation; prostaglandin endoperoxide synthase; steroid hormone biosynthesis; steroid hormone metabolism; tissue /cell culture; tissue support frame

An estimated 60-70 percent of human breast cancers are associated with sex hormone exposure. Approximately 60 percent of all breast cancer patients have hormone-dependent breast cancer, which contains estrogen receptors and requires estrogen for tumor growth. The possible biochemical roles of estrogens in the development of breast cancers remains to be fully elucidated. This research focuses on examination of the role of steroid hormones and estrogen biotransformations in breast cancer etiology. Our hypothesis is that alterations in the breast cancer tissue microenvironment can influence the extent of estrogen biosynthesis and metabolism, result in altered levels of hormonally active estrogens and their metabolites, and therefore influence breast tumor development and growth. Biochemical and molecular examination of this hypothesis in vitro will be performed in human patient breast tissue specimens and in several human breast cancer cell systems currently in use in our laboratories. These breast cell systems include immortalized transformed breast epithelial cells grown in monolayers on plastic or on extracellular matrix support (ecm such as Matrigel TM or collagen I) and cultures of human breast stromal cells isolated from breast cancer tissues or normal breast tissues. Traditional culturing of cells on plastic promotes maximal proliferation, while culturing cells on collagen or on Matrigel supports cell maintenance and subsequent differentiation. The specific aims of the research on the various human breast cell systems are (1) to examine the extent of aromatase (CYP19) expression and cyclooxygenase (COX-1 and COX-2) expression in human breast cancer specimens, (2) to examine enzyme expression and the extent of formation of E2 in human breast cancer cell systems, (3) to examine the extent of formation of oxidative metabolites in human breast cancer cell systems, and (4) to determine the biological consequences of estrogen biosyntesis and metabolism in the human breast cell systems.

据估计，60%-70%的人类乳腺癌与 性激素暴露 大约60%的乳腺癌 患者患有乳腺癌依赖性乳腺癌， 肿瘤生长需要雌激素。可能的 雌激素在乳腺癌发生中的生化作用 还有待于充分阐明。 本研究的重点是考试 类固醇激素和雌激素生物转化在 乳腺癌的病因 我们的假设是， 乳腺癌组织微环境可以影响 雌激素的生物合成和代谢，导致 具有生殖活性的雌激素及其代谢物，因此 影响乳腺肿瘤的发育和生长。 生化和 将在体外对这一假设进行分子检测， 人患者乳腺组织标本和几种人乳腺癌中 我们实验室目前使用的细胞系统。 这些乳腺细胞 系统包括永生化的转化乳腺上皮细胞， 在塑料或细胞外基质支持物（ECM， 如MatrigelTM或胶原I）和人乳腺基质细胞的培养物 分离自乳腺癌组织或正常乳腺组织。 传统的塑料培养细胞促进最大的 增殖，同时在胶原或基质胶支持物上培养细胞 细胞维持和随后的分化。 的具体目标 对各种人类乳腺细胞系统的研究是（1）检查 芳香化酶（CYP 19）表达和环氧合酶（考克斯-1和 考克斯-2）在人乳腺癌标本中的表达，（2）检测 人乳腺组织中E2的表达和形成程度 癌细胞系统，（3）检查氧化的形成程度 人乳腺癌细胞系统中的代谢物，以及（4）确定 雌激素生物合成和代谢的生物学后果， 人类乳腺细胞系统。