Estrogen Biotransformations and Breast Cancer Etiology

描述（由申请人提供）：癌症是30至54岁妇女的主要死因。据估计，2001年将诊断出186，000例新的乳腺癌病例，美国将有42，000名妇女死于乳腺癌。目前，九分之一的美国女性在一生中会患上乳腺癌。这项研究的重点是检查类固醇激素在乳腺癌病因中的作用。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，其中含有雌激素受体，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影响（积极或消极）在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生物合成和代谢的程度，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育和生长。本实验室最近的研究表明，在目前的拨款支持的CYP 19基因的表达和考克斯基因的表达之间的关系。芳香化酶和环氧合酶系统之间的这种显著关系表明，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了雌激素依赖性乳腺癌的发展。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对这一假设进行体外生物化学和分子学检查。具体目标是：（1）通过关联酶活性和通过使用考克斯抑制剂或反义方法调节环加氧酶来检查人乳腺细胞培养系统中芳香酶和环加氧酶之间的关系。(2)使用选择性膜EP激动剂和拮抗剂以及通过PPAR发挥作用的药理学药物，研究这些生物合成途径相互作用的潜在生化机制。(3)检测人乳腺癌标本中芳香化酶和环氧化酶的表达水平。

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.