PROGESTERONE RECEPTORS AND BREAST CANCER

描述（由申请人提供）：乳腺癌是由雌激素(E)和黄体酮(P)作用引起的女性疾病。虽然卵巢切除术具有保护作用，但与仅使用雌激素相比，雌激素+P激素替代疗法会增加患乳腺癌的风险。这表明P单独或与E一起促进肿瘤。尽管许多研究都只关注E或P的作用，但我们认为必须了解这两种激素是如何协同作用的。E和P激活雌激素（ER）或孕激素（PR）受体。两种PR亚型PR- a和PR- b在正常乳腺中是相等的，但在癌症中却失调。他莫昔芬治疗的富PR-A肿瘤患者比富PR-B肿瘤患者复发更快。重要的是，在P存在或不存在的情况下，PR-A和PR-B对E依赖性肿瘤生长的影响是不同的。我们假设，在P存在或不存在的情况下，PR-A和PR-B对E和ER对肿瘤的影响是不同的，PR-A尤其有害。目的1。pr - a与PR-B的配体依赖性（LD）和非配体依赖性（LI）转录机制。在P存在的情况下，PR-A和PR-B对基因转录的影响不同，PR-B作用更强。在没有P的情况下，PR-A和PR-B也不同，PR-A更强。我们还发现，除了孕酮反应元件（PRE）外，LD和LI pr调控的启动子还含有共反应元件（coRE）。本文旨在剖析PRE和coRE在PR-A和PR-B差异基因调控中的作用，并探讨LI基因调控的机制。目标2。PR亚型和体内LI和LD对E调控肿瘤生物学和治疗的影响。我们的初步数据，使用ER+， e依赖的异种移植物在卵巢切除的非p补充小鼠中，显示PR-A的存在抑制肿瘤生长。这个目的是问：为什么PR-A+肿瘤比PR-B+肿瘤小？PR如何影响肿瘤对抗雌激素的反应？PR为何阻断紫杉烷细胞凋亡？目标3。ER和PR及其激素在乳腺癌细胞转移和生长中的作用。ER+、PR+乳腺癌的转移是女性的主要杀手，但传统的“智慧”认为这类肿瘤不会转移。我们的模型显示ER+、PR+肿瘤有转移。本研究旨在建立e依赖性ER+、PR+转移性乳腺癌的新模型，并明确类固醇受体和激素在这一过程中的作用。总之，我们将开发新的模型来验证假设，即PR，即使在没有P的情况下，也会改变ER+肿瘤细胞的行为，PR- a增加肿瘤的侵袭性并且有害。

DESCRIPTION (provided by applicant): Breast cancer is a disease of women due to the actions of estrogens (E) and progesterone (P). While oophorectomy is protective, hormone replacement therapy with E+P increases breast cancer risk compared to E-only. This implicates P, either alone or with E, in tumor promotion. Though many studies address the actions of E or P alone, we contend that one must understand how these two hormones work together. E and P activate estrogen (ER) or progesterone (PR) receptors. Two PR isoforms, PR-A and PR-B, are equal in the normal breast but dysregulated in cancers. Tamoxifen treated patients whose tumors are PR-A rich relapse faster than patients with PR-B rich tumors. Importantly, PR-A and PR-B differentially influence E-dependent tumor growth in either the presence or absence of P. We postulate that PR-A and PR-B in the absence or presence of P, differentially influence effects of E and ER on tumors and that PR-A are especially harmful. AIM 1. Mechanisms of ligand dependent (LD) and ligand independent (LI) transcription by PR.A vs. PR-B. In the presence of P, PR-A and PR-B exert different effects on gene transcription with PR-B more powerful. In the absence of P, PR-A and PR-B are also different with PR-A more powerful. We also show that in addition to Progesterone Response Elements (PRE), LD and LI PR-regulated promoters contain co-Response elements (coRE). This aim dissects the role of PRE and coRE in differential gene regulation by PR-A and PR-B, and addresses mechanisms of LI gene regulation. AIM 2. PR isoforms and in vivo LI and LD effects on E regulated tumor biology and therapeutics. Our preliminary data, using ER+, E-dependent xenografts in ovariectomized non-P supplemented mice, show that presence of PR-A suppresses tumor growth. This aim asks: Why are PR-A+ tumors smaller than PR-B+ ones? How do PR influence tumor responses to antiestrogens? Why do PR block apoptosis by Taxanes? AIM 3. The role of ER and PR and their hormones in breast cancer cell metastasis and growth. Metastasis of ER+, PR+ breast cancers is the major killer of women yet conventional "wisdom" holds that such tumors do not metastasize. Our models show metastasis of ER+, PR+ tumors. This aim develops new models of E-dependent ER+, PR+ metastatic breast cancer and defines the role of steroid receptors and hormones in this process. In sum, we will develop new models to test the hypothesis that PR, even in the absence of P, modify ER+ tumor cell behavior, and that PR-A increase tumor aggressiveness and are harmful.