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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Reproductive Endocrinology Study Section (REN)
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Sathyamoorthy, Neeraja
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University of Wisconsin Madison
Schools of Veterinary Medicine
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Asher, Jennifer M; O'Leary, Kathleen A; Rugowski, Debra E et al. (2012) Prolactin promotes mammary pathogenesis independently from cyclin D1. Am J Pathol 181:294-302
Arendt, Lisa M; Rugowski, Debra E; Grafwallner-Huseth, Tara A et al. (2011) Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer. Breast Cancer Res 13:R11
Carver, Kristopher C; Piazza, Timothy M; Schuler, Linda A (2010) Prolactin enhances insulin-like growth factor I receptor phosphorylation by decreasing its association with the tyrosine phosphatase SHP-2 in MCF-7 breast cancer cells. J Biol Chem 285:8003-12
Sakamoto, K; Triplett, A A; Schuler, L A et al. (2010) Janus kinase 2 is required for the initiation but not maintenance of prolactin-induced mammary cancer. Oncogene 29:5359-69
Arendt, Lisa M; Grafwallner-Huseth, Tara L; Schuler, Linda A (2009) Prolactin-growth factor crosstalk reduces mammary estrogen responsiveness despite elevated ERalpha expression. Am J Pathol 174:1065-74
Carver, Kristopher C; Arendt, Lisa M; Schuler, Linda A (2009) Complex prolactin crosstalk in breast cancer: new therapeutic implications. Mol Cell Endocrinol 307:1-7
Piazza, Timothy M; Lu, Juu-Chin; Carver, Kristopher C et al. (2009) SRC family kinases accelerate prolactin receptor internalization, modulating trafficking and signaling in breast cancer cells. Mol Endocrinol 23:202-12
Arendt, Lisa M; Evans, Lindsay C; Rugowski, Debra E et al. (2009) Ovarian hormones are not required for PRL-induced mammary tumorigenesis, but estrogen enhances neoplastic processes. J Endocrinol 203:99-110
Carver, Kristopher C; Schuler, Linda A (2008) Prolactin does not require insulin-like growth factor intermediates but synergizes with insulin-like growth factor I in human breast cancer cells. Mol Cancer Res 6:634-43
Arendt, Lisa M; Schuler, Linda A (2008) Prolactin drives estrogen receptor-alpha-dependent ductal expansion and synergizes with transforming growth factor-alpha to induce mammary tumors in males. Am J Pathol 172:194-202

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