Mechanisms of the Hormonal Prevention of Breast Cancer

乳腺癌是美国女性最常见的癌症。在大多数流行病学研究中，一个一致的发现是，早期足月怀孕对乳腺癌发病率具有保护作用。在动物模型中，可以通过短期接触低剂量的雌激素和孕激素来模拟怀孕提供的保护。该计划项目的长期目标是了解类固醇激素是如何被机体自然利用来防止乳腺癌的发展的。本计划项目申请中描述的方法是独一无二的，因为它侧重于有限暴露低剂量的自然产生的激素，以永久降低乳腺癌的发展风险。这种多学科方法研究的基本模型是激素诱导预防近交系Wistar-Furth雌性大鼠乳腺癌。该方案项目由3个项目和4个核心设施组成。项目1研究了P53的激素调节机制，以及它作为激素诱导的抗癌作用的媒介的作用。项目2检查中心体放大作为转化早期阶段的细胞标记，以及它被蛋白激酶BTAK调节。项目3研究成熟乳腺的易感和耐药状态所特有的基因表达、功能和定位。每个项目都依赖于核心设施的实验和智力贡献；管理/生物统计学核心、动物核心、显微镜和分子细胞学核心以及组织病理学核心。该计划项目的成功有赖于个体研究人员在肿瘤生物学、生殖生物学、发育生物学、分子内分泌学和分子生物学领域提供的互补专业知识。对激素诱导的生长和分化所涉及的基本生物学事件的分子理解将为开发预防人类乳腺癌的新方法提供理论基础。

Breast cancer is the most frequent cancer in women in the United States. A consistent finding in most epidemiological studies has been the protective effect of an early full term pregnancy on the incidence of breast cancer. In animal models the protection afforded by pregnancy can be mimicked by short-term exposure to low doses of estrogens and progestins. The long-term goals of this program project are to understand how steroid hormones are used naturally by the organism to prevent the development of breast cancer. The approach described in this Program Project application is unique as it focuses on a limited exposure of low doses of naturally-occurring hormones to permanently decrease the risk of breast cancer development. The basic model studied in this multi-disciplinary approach is hormone-induced prevention of N-methyl-N-nitrosourea -induced breast cancer in the inbred Wistar-Furth female rat. The Program Project consists of 3 Projects and 4 Core facilities. Project 1 examines the mechanisms of hormonal regulation of p53 and its role as a mediator of hormone- induced resistance to carcinogenesis. Project 2 examines centrosome amplification as a cellular marker for early stages of transformation and its regulation by BTAK, a protein kinase. Project 3 examines specific gene expression, function and localization that is unique to the susceptible and resistant states of the mature mammary gland. Each project is dependent upon the experimental and intellectual contributions of the Core facilities; the Administration/Biostatistics Core, Animal Core, Microscopy and Molecular Cytology Core, and Histopathology Core. The success of this Program Project depends on the complementary expertise provided by the individual investigators in the areas of tumor biology, reproductive biology, developmental biology, molecular endocrinology and molecular biology. The molecular understanding of the fundamental biological events involved in hormone-induced growth and differentiation will provide a rationale for developing new approaches for preventing human breast cancer.