Estrogen Biotransformations and Breast Cancer Etiology

雌激素生物转化和乳腺癌病因学

• 批准号: 6606205
• 负责人: ROBERT W BRUEGGEMEIER
• 金额: $ 27.73万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606205
• 关键词: aromatase; biotransformation; breast neoplasms; clinical research; disease /disorder etiology; eicosanoids; enzyme activity; enzyme inhibitors; estrogen receptors; gene expression; hormone biosynthesis; hormone regulation /control mechanism; hormone related neoplasm /cancer; human tissue; immunocytochemistry; laser capture microdissection; messenger RNA; neoplasm /cancer genetics; northern blottings; peroxisome proliferator activated receptor; prostaglandin endoperoxide synthase; radioimmunoassay; steroid hormone biosynthesis; steroid hormone metabolism; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Cancer is the leading cause of death among women between the ages of 30 and 54. An estimated 186,000 new cases of breast cancer will be diagnosed, and 42,000 women in the U.S. will die from breast cancer in 2001. Currently, one out of nine American women will develop breast cancer in her lifetime. This research focuses on examination of the role of steroid hormones in breast cancer etiology. An estimated 60-70% of human breast cancers are associated with sex hormone exposure. Approximately 60% of all breast cancer patients have hormone-dependent breast cancer, which contains estrogen receptors and requires estrogen for tumor growth. The chemical forms of estrogen molecules and their relative concentrations in the breast tissue can influence breast epithelial cancer cell growth. Furthermore, the ratios of various endogenous estrogen molecules can influence (either positively or negatively) other cell types in the breast tissue environment, such as stromal cells and vascular endothelial cells. 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 biologically active estrogens and their metabolites, and therefore influence breast tumor development and growth. Recent studies in our laboratory supported by the current grant demonstrated a relationship between CYP19 gene expression and the expression of COX genes. This significant relationship between the aromatase and cyclooxygenase enzyme systems suggests that autocrine and paracrine mechanisms may be involved in hormone-dependent breast cancer development via growth stimulation from local estrogen biosynthesis. 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. The specific aims are: (1) To examine the relationship between aromatase and cyclooxygenases in human breast cell culture systems by correlating enzyme activities and by modulating cyclooxygenases using COX inhibitors or antisense approaches. (2) To investigate potential biochemical mechanisms for the interactions of these biosynthetic pathways using selective membrane EP agonists and antagonists and pharmacological agents acting through PPAR. (3) To measure cellular levels of aromatase expression and cyclooxygenases expression in human breast cancer specimens.

描述（由申请人提供）：癌症是30至54岁妇女死亡的主要原因。据估计，2001年将有18.6万新的乳腺癌病例被诊断出来，42000名美国妇女将死于乳腺癌。目前，每9名美国女性中就有1人会在一生中患上乳腺癌。本研究的重点是检查类固醇激素在乳腺癌病因学中的作用。据估计，60-70%的人类乳腺癌与性激素暴露有关。大约60%的乳腺癌患者患有激素依赖性乳腺癌，这种乳腺癌含有雌激素受体，肿瘤生长需要雌激素。雌激素分子的化学形式及其在乳腺组织中的相对浓度可以影响乳腺上皮癌细胞的生长。此外，各种内源性雌激素分子的比例可以（积极或消极地）影响乳腺组织环境中的其他细胞类型，如基质细胞和血管内皮细胞。我们的假设是，乳腺癌组织微环境的改变可以影响雌激素的生物合成和代谢程度，导致生物活性雌激素及其代谢物水平的改变，从而影响乳腺肿瘤的发生和生长。我们实验室最近的研究得到了当前拨款的支持，证明了CYP19基因表达与COX基因表达之间的关系。芳香化酶和环加氧酶系统之间的这种重要关系表明，自分泌和旁分泌机制可能通过局部雌激素生物合成的生长刺激参与激素依赖性乳腺癌的发展。这一假设的体外生化和分子检查将在人类患者乳腺组织标本和我们实验室目前使用的几种人类乳腺癌细胞系统中进行。具体目的是：(1)通过关联酶活性和使用COX抑制剂或反义方法调节环加氧酶来研究人乳腺细胞培养系统中芳香化酶和环加氧酶之间的关系。(2)利用选择性膜EP激动剂和拮抗剂以及通过PPAR作用的药理学药物，研究这些生物合成途径相互作用的潜在生化机制。(3)测定人乳腺癌标本中芳香化酶和环氧合酶的细胞表达水平。