Long Term Increased Expression of the Short Form Ib Prolactin Receptor in PC-3 Human Prostate Cancer Cells Decreases Cell Growth and Migration, and Causes Multiple Changes in Gene Expression Consistent With Reduced Invasive Capacity

BACKGROUND. We have shown that treatment of human prostate cancer cells with the selective prolactin (PRL) receptor modulator, S179D PRL, inhibits growth in vitro, and the initiation and growth of xenografts in vivo. S179D PRL treatment also upregulates expression of the short form 1b (SF1b) PRL receptor, activation of which upregulates expression of the cell cycle-regulating protein, p21. METHODS. We examined the consequences of long term increased expression and activation of SF1b, at levels comparable to those resulting from treatment with S179D PRL, by creating PC-3-derived stable cell lines expressing a constitutively active form of SF1b, Delta S2 SF1b. RESULTS. Increased expression of Delta S2 SF1b decreased growth and migration of the cells. This was accompanied by an increase in cell-matrix interactions, and cell-cell aggregation when cells were plated on basement membrane components. Real-time PCR evaluated the expression of genes related to invasive capacity. Of particular interest was decreased expression of the protease, urokinase-type plaminogen activator, and its receptor, uPAR, and increased expression of its inhibitors, PAI-1 and 2. Also decreased in cells with increased expression of Delta S2 SF1b was expression of basic fibroblast growth factor and vascular endothelial growth factor. CONCLUSION. We conclude that at least part of the beneficial effects of S179D PRL is the result of increased expression of SF1b, and that the effects of increased expression and activation of SF1b continue to be of potential benefit in the long term. Prostate 70: 37-47, 2010. (c) 2009 Wiley-Liss. Inc,