Estrogen Biotransformations and Breast Cancer Etiology

雌激素生物转化和乳腺癌病因学

基本信息

批准号：
7084398
负责人：
ROBERT W BRUEGGEMEIER
金额：
$ 27.08万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-18 至 2009-06-30
项目状态：
已结题

项目摘要

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岁的妇女中的主要死亡原因。估计将诊断出186,000例新的乳腺癌病例，在2001年，美国有42,000名妇女死于乳腺癌。目前，她一生中有9名美国妇女中有1名将患上乳腺癌。这项研究重点是检查类固醇激素在乳腺癌病因中的作用。估计有60-70％的人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，需要雌激素才能进行肿瘤生长。雌激素分子的化学形式及其在乳腺组织中的相对浓度会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率可能会影响乳腺组织环境中的其他细胞类型（例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会影响雌激素生物合成和代谢的程度，从而导致生物活性活性雌激素及其代谢水平改变，从而影响乳腺肿瘤的发育和生长。当前赠款支持我们的实验室的最新研究表明，CYP19基因表达与COX基因的表达之间存在关系。芳香酶和环氧酶系统之间的这种重要关系表明，通过局部雌激素生物合成的生长刺激，自分泌和旁分泌机制可能与激素依赖性乳腺癌发展有关。在人类患者乳房组织标本以及目前正在我们实验室中使用的几种人类乳腺癌细胞系统中，将对这种假设进行生化和分子检查。具体目的是：（1）通过使用COX抑制剂或反义方法将酶活性和通过调节环氧合酶来检查人类乳细胞培养系统中芳香酶和环氧酶之间的关系。（2）研究使用选择性膜性ep激动剂和拮抗剂和通过PPAR作用的药理学剂进行这些生物合成途径相互作用的潜在生化机制。（3）测量人类乳腺癌标本中芳香酶表达和环氧酶表达的细胞水平。