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Signaling and Regulation

Prolactin Does Not Require Insulin-Like Growth Factor Intermediates but Synergizes with Insulin-Like Growth Factor I in Human Breast Cancer Cells

Cellular and Molecular Biology Program, Biotechnology Training Program, and Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin

Requests for reprints: Linda A. Schuler, Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706. Phone: 608-263-9825; Fax: 608-263-3926. E-mail: schulerl{at}svm.vetmed.wisc.edu

Insulin-like growth factor (IGF)-II is a required intermediate for prolactin-induced up-regulation of cyclin D1 and proliferation in normal murine mammary epithelial cells in vivo and in vitro. However, we have recently shown that prolactin can rapidly induce cyclin D1 protein expression and subsequent proliferation in the MCF-7 human breast cancer cell line, suggesting that prolactin actions can be independent of IGFs in breast disease. Here, we investigate the relationship between these factors and show that prolactin up-regulated transcript levels of both IGF-I and IGF-II, but only after increases in cyclin D1 protein were observed. Moreover, prolactin increased cyclin D1 in the presence of the IGF-I receptor neutralizing antibody IR3. However, on cotreatment, IGF-I and prolactin elicited cooperative phosphorylation of extracellular signal–regulated kinases 1 and 2 and protein kinase B/AKT, but not signal transducer and activator of transcription 5. This interaction extended to increased activation of activating protein-1 enhancer elements, phosphorylation of glycogen synthase kinase 3β, induction of cyclin D1, and ultimately, increased cell number. It also increased invasive behavior, which correlated with elevated matrix metalloproteinase-2 transcript levels. Interestingly, prolactin augmented phosphorylation at Tyr¹¹³⁵ and Tyr¹¹³⁶ of IGF-I receptor on cotreatment with IGF-I, although prolactin alone had no effect. Together, these data indicate that strong cooperative cross talk between prolactin and IGF-I augments biological processes associated with neoplastic progression, with implications for therapeutic strategies. (Mol Cancer Res 2008;6(4):634–43)