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Submitted on May 4, 2004
Accepted on August 10, 2004
Molecular and Environmental Toxicology Program (J.H.G., L.A.S.), Department of Comparative Biosciences (D.E.R., M.D.S., J.J.W., L.A.S.), University of Wisconsin-Madison, Madison, WI 53706
* To whom correspondence should be addressed. E-mail: schulerl{at}svm.vetmed.wisc.edu.
The importance of prolactin (PRL) in physiologic proliferation and differentiation of the mammary gland, together with high levels of PRL receptors in breast tumors, the association of circulating PRL with incidence of breast cancer, and the recognition of locally produced PRL, point to the need for greater understanding of PRL actions in mammary disease. Although PRL has been shown to activate multiple kinase cascades in various target cells, relatively little is known of its signaling pathways in the mammary gland apart from Jak2/STAT5, particularly in tumor cells. Another potential effector is activating protein-1 (AP-1), a transcription complex which regulates processes essential for neoplastic progression, including proliferation, survival and invasion. We demonstrate that PRL activates AP-1 in MCF-7 cells, detectable at 4 h and sustained for at least 24 h. Although Jak2 and ERK1/2 are the primary mediators of PRL-induced signals, c-Src, phosphatidylinositol 3'-kinase, protein kinase C and other MAP kinases contribute to maximal activity. PRL activation of these pathways leads to increased c-Jun protein and phosphorylation, JunB protein, and phosphorylation of c-Fos, elevating the levels of AP-1 complexes able to bind DNA. These active AP-1 dimers may direct expression of multiple target genes, mediating some of PRL's actions in mammary disease.
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