Mammary Prolactin Production and Breast Cancer

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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.