Mammary Prolactin Production and Breast Cancer

描述（由申请人提供）：虽然催乳素（PRL）在正常乳腺中发挥重要作用，但其在人类乳腺癌中的作用仍知之甚少。尽管在人类肿瘤中PRL受体升高，但将循环PRL与疾病相关的流行病学研究一直不一致，溴隐亭治疗阻断垂体PRL没有一致的临床效果。然而，在这些研究中，未涉及人乳腺组织中PRL的局部产生，允许自分泌/旁分泌活性。在上一个资助期，我们发现PRL通过调节细胞周期蛋白D1和p21的表达在体外刺激乳腺细胞周期，并描述了一个协调这一过程的信号通路网络。此外，体内乳腺上皮细胞内PRL的过表达导致肿瘤发生，并且PRL影响TGF α诱导的乳腺癌发生以减少肿瘤潜伏期。我们的研究结果支持PRL在乳腺癌增殖增加中的作用，并提供模型来检查这种疾病中的机制和与其他因素的相互作用。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，并激活重叠但不同的信号传导途径，协同促进乳腺肿瘤的发生和进展。使用我们独特的模型，包括已被工程化为PRL产生缺陷或条件性过表达PRL的MCF 7细胞衍生的亚系，以及我们在非乳腺调节的乳腺富集启动子控制下过表达PRL、TGF α或PRL和TGF α的转基因小鼠，我们提出：比较PRL和E2在体外的作用，并检测它们在细胞周期动力学、细胞周期蛋白D1信号传导以及导致增殖的信号串扰中的相互作用。第二章：使用我们的过表达PRL和/或TGF α的转基因小鼠，探索肿瘤发生过程中E2和PRL之间的体内相互作用，以检查E2和ER α对肿瘤发展和进展的影响，并鉴定在E2存在或不存在下有活性的靶基因和信号通路，以及3：利用细胞周期蛋白D1-/-小鼠品系，检查细胞周期蛋白D1在E2调节PRL、TGF α和PRL/TGF α诱导的乳腺癌发生中的作用。这些研究将增加我们对这些因素如何在乳腺肿瘤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.