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Submitted on July 2, 2003
Accepted on September 3, 2003
1 Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706; Division of Biomedical Sciences, University of California, Riverside, California 92521
* To whom correspondence should be addressed. E-mail: schulerl{at}svm.vetmed.wisc.edu.
Posttranslational modifications of prolactin (PRL), including phosphorylation, vary with physiologic state and alter biologic activity. In light of the growing evidence for a role for PRL in proliferation in mammary cancer, we examined the ability of a mimic of phosphorylated human prolactin, S179D-PRL, to initiate signals to several pathways in mammary tumor cells alone and in combination with unmodified PRL. Unmodified PRL employed multiple pathways to increase cellular proliferation and cyclin D1 levels in PRL-deficient MCF-7 cells. S179D-PRL was a weak agonist compared with unmodified PRL with regard to cellular proliferation, cyclin D1 levels, and phosphorylation of STAT 5 and ERKs. However, S179D-PRL was a potent antagonist of unmodified PRL to these endpoints. In contrast to the reduced levels of the long isoform of the PRLR observed in response to a 3d incubation with unmodified PRL, S179D-PRL upregulated expression of this isoform, 4 fold. These studies support the utility of this mutant as a PRL antagonist to proliferative signals in mammary epithelial cells, including a potential role in breast cancer therapeutics.
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