PROGESTERONE RECEPTOR AND BREAST CANCER

乳腺癌被认为是女性中最常见的恶性肿瘤 在北美，目前估计终身风险为1/ 八 最重要的是，生殖史，或者更具体地说， 类固醇激素状态已被证明是一个重要的风险因素。 最近，我产生了一个孕激素受体（PR）敲除（PRKO）小鼠， 已经证明孕酮（P）及其受体PR， 是正常乳腺增生所必需的， 分化 P在乳腺肿瘤发生中的作用已被证实， 这是一个多年来一直存在争议的问题，主要是因为P可以 预防或抑制乳腺肿瘤发生。 为了澄清复杂的 P与乳腺肿瘤发生的时间关系 小鼠将被用来确定是否P诱导增殖 信号在乳腺癌中的作用， 消除PR功能对乳腺肿瘤进展的影响。 这项建议的具体目的是：1）评估是否 PR功能改变小鼠对致癌物诱导的 乳腺肿瘤发生的形态学、组织学和分子生物学研究 2）确定公关职能是否在发展中发挥作用 Grunder小鼠表现出的激素依赖性乳腺肿瘤， 定义公关是否参与了这些进展 将肿瘤转化为激素非依赖性表型;以及3）定义不同的 乳腺上皮和间质来源的PR群体对 利用相互乳腺进行乳腺发育和肿瘤发生 移植技术 除了推进我们目前的 了解P对乳腺肿瘤发生的作用，信息 这些研究将有助于设计有效的战略， 乳腺癌的预防和治疗以及促进 重新评价目前使用孕激素避孕的情况， 绝经后激素替代疗法

Breast cancer is recognized as the most prevalent malignancy among women in North America with a life time risk currently estimated to be one in eight. Most importantly, reproductive history or more specifically steroid hormonal status has been shown to be an important risk factor. Recently, I generated a progesterone receptor (PR) knockout (PRKO) mouse that has demonstrated that progesterone (P), and its receptor, the PR, are absolutely required for normal mammary gland proliferation and differentiation. The involvement of P in mammary tumorigenesis has been a matter of controversy for several years mainly because P can protentiate or inhibit mammary tumorigenesis. To clarify the complex temporal relationship between P and mammary tumorigenesis, the PRKO mouse will be utilized to determine whether the P indued-proliferative signal has a role to play in breast cancer by investigating the effects of removing PR function on mammary tumor progression. The specific aims of this proposal are to: 1) evaluate whether removal of PR function alters murine susceptibility to carcinogen-induced mammary tumorigenesis at the morphological, histological, and molecular level; 2) determine whether PR function has a role in the development of hormone dependent mammary tumors exhibited by the Grunder mouse and define whether the PR has an involvement in the progression of these tumors to a hormone independent phenotype; and 3) to define the distinct effects of mammary epithelial and stromal derived PR populations on mammary development and tumorigenesis by using reciprocal mammary gland transplantation technology. Apart from advancing our current understanding of P's contribution to mammary tumorigenesis, information from these studies will aid in the design of effective strategies for breast cancer prevention and treatment as well as prompting a reevaluation of the current use of progestins in contraception and postmenopausal hormonal replacement therapies.