Mammary Prolactin Production and Breast Cancer

描述（由申请人提供）：虽然催乳素（PRL）在正常乳腺中起重要作用，但其在人类乳腺癌中的作用尚不清楚。尽管人类肿瘤中PRL受体升高，但流行病学研究表明循环PRL与疾病之间的关系并不一致，溴隐肽阻断垂体PRL的治疗也没有一致的临床效果。然而，在这些研究中，没有解决人类乳腺组织中局部产生PRL，允许自分泌/旁分泌活动的问题。在之前的研究中，我们发现PRL通过调节cyclin D1和p21的表达来刺激体外乳腺细胞周期，并描述了协调这一过程的信号通路网络。此外，体内乳腺上皮细胞中PRL的过表达可导致肿瘤发生，PRL可影响tgfa诱导的乳腺癌发生，从而减少肿瘤潜伏期。我们的研究结果支持PRL在乳腺癌增殖增加中的作用，并为研究该疾病的机制及其与其他因素的相互作用提供了模型。假设：PRL和雌二醇（E2）通过刺激细胞周期调节因子的表达和活性，导致细胞增殖增加，激活重叠但不同的信号通路，协同促进乳腺肿瘤的发生和进展。利用我们独特的模型，包括MCF7细胞衍生的亚群，这些亚群被设计成缺乏PRL的产生或有条件地过度表达PRL，以及我们的转基因小鼠，过度表达PRL， TGFa，或PRL和TGFa在非激素调节的乳腺富集启动子的控制下，我们提出：1：比较PRL和E2在体外的作用，并检查它们在细胞周期动力学中的相互作用，细胞周期蛋白D1的信号传导，以及导致增殖的信号串扰。2:探索E2和光杆载荷之间的相互作用在活体内肿瘤发生期间,使用我们的转基因老鼠overexpressing PRL和/或TGFa,检查E2和肿瘤发展和时代发展的影响,并确定目标基因和信号通路,活跃在E2的存在与否,和3:检查细胞周期蛋白D1的角色在PRL E2调制,TGFa,和PRL / TGFa-induced乳腺致癌作用,利用细胞周期蛋白D1 - / -小鼠压力。这些研究将增加我们对这些因素如何在乳腺肿瘤的发病机制中合作的理解，并设计临床有用的方法。

DESCRIPTION (provided by applicant): While prolactin (PRL) plays important roles in the normal mammary gland, its role in human breast cancer remains poorly understood. Despite elevated PRL receptors in human tumors, epidemiological studies correlating circulating PRL to disease have been inconsistent, and bromocriptine treatment to block pituitary PRL had no consistent clinical effect. However, local production of PRL in human breast tissue, permitting autocrine/paracrine activity, was not addressed in these studies. In the previous grant period, we showed that PRL stimulates the mammary cell cycle in vitro by modulating the expression of cyclin D1 and p21, and described a web of signaling pathways that orchestrate this process. Further, overexpression of PRL within mammary epithelial cells in vivo leads to tumorigenesis, and PRL influences TGFa-induced mammary carcinogenesis to decrease tumor latency. Our findings support a role for PRL in the increased proliferation in breast cancer, and provide models to examine mechanisms and interactions with other factors in this disease. Hypothesis: PRL and estradiol (E2) synergistically promote mammary tumor development and progression, via stimulation of expression and activity of cell cycle regulators leading to increased cellular proliferation, and activation of overlapping, but distinct signaling pathways. Using our unique models, including MCF7 cell-derived sublines that have been engineered to be deficient in PRL production or to conditionally overexpress PRL, and our transgenic mice that overexpress PRL, TGFa, or PRL and TGFa under the control of a non-hormonally regulated mammary enriched promoter, we propose to: 1: Compare the actions of PRL and E2 in vitro, and examine their interactions in cell cycle kinetics, signaling to cyclin D1, as well as signaling crosstalk leading to proliferation. 2: Explore interactions between E2 and PRL in vivo during tumorigenesis, using our transgenic mice overexpressing PRL and/or TGFa, to examine the effect of E2 and ERa on tumor development and progression, and identify target genes and signaling pathways that are active in the presence or absence of E2, and 3: Examine the role of cyclin D1 in E2 modulation of PRL, TGFa, and PRL/TGFa-induced mammary carcinogenesis, taking advantage of the cyclin D1-/- mouse strain. These studies will increase our understanding of how these factors may cooperate in the pathogenesis of mammary neoplasia, and design of clinically useful approaches.