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，其终生风险目前估计为 八。最重要的是，生育史，或者更具体地说 类固醇激素状态已被证明是一个重要的危险因素。 最近，我培育了一只孕激素受体(PR)基因敲除(PRKO)小鼠 这表明孕酮(P)及其受体PR， 对于正常的乳腺增殖和 差异化。P蛋白在乳腺肿瘤发生中的作用 几年来一直存在争议的问题，主要是因为P可以 保护或抑制乳腺肿瘤的发生。为了澄清这个情结 P与乳腺肿瘤发生、PRKO的时间关系 小鼠将被用来确定P诱导的增殖 通过研究Signal在乳腺癌中的作用 去除PR功能对乳腺肿瘤进展的影响。 该提案的具体目的是：1)评估是否移除 PR功能改变小鼠对致癌物诱导的敏感性 乳腺肿瘤发生的形态学、组织学和分子生物学研究 级别；2)确定公关功能是否在发展中起作用 表现为荷尔蒙依赖性乳腺肿瘤的小鼠和 定义公关是否参与这些项目的进展 肿瘤到激素不依赖的表型；以及3)定义不同的 乳腺上皮和间质来源的PR群体对人乳腺癌细胞生长的影响 利用对生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在乳腺肿瘤发生、发展中的作用 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使人们 孕激素在避孕和避孕中应用现状的再评价 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.