Estrogen Biotransformations and Breast Cancer Etiology

描述(申请人提供)：癌症是30岁至54岁女性的主要死因。据估计，2001年美国将新增18.6万例乳腺癌病例，4.2万名妇女将死于乳腺癌。目前，每九名美国女性中就有一名在有生之年患上乳腺癌。本研究旨在探讨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型乳腺癌，这种乳腺癌含有雌激素受体，需要雌激素才能使肿瘤生长。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例可以影响(积极或消极)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展和生长。我们实验室最近的研究证实了细胞色素P19基因的表达与环氧合酶基因的表达之间的关系。芳香酶和环氧合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而参与激素依赖型乳腺癌的发展。这一假说的生化和分子检测将在体外对人类患者的乳腺组织样本和我们实验室目前使用的几种人类乳腺癌细胞系统进行。其具体目的是：(1)通过关联酶活性和使用COX抑制剂或反义方法调节环氧合酶，来研究人乳腺细胞培养体系中芳香酶和环氧合酶之间的关系。(2)使用选择性的膜EP激动剂和拮抗剂，以及通过PPAR作用的药物，探讨这些生物合成途径相互作用的潜在生化机制。(3)检测乳腺癌组织中芳香化酶和环氧合酶的细胞表达水平。

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.