Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation

The involvement of human prolactin (hPRL) in breast cancer has been recentl y reconsidered based on its autocrine/paracrine proliferative effect descri bed in human mammary tumor epithelial cells. Therefore, there is growing in terest in the development of potent hPRL antagonists that may inhibit this effect. We previously designed hPRL analogs displaying antagonistic propert ies in a human transcriptional bioassay. We now report that the most potent of those analogs, G129R-hPRL, antagonizes all hPRL-induced effects analyse d in various breast cancer cell lines, including cell proliferation. The an alog per sc lacks intrinsic agonistic activity on PRL receptor-activated si gnaling cascades, cell proliferation and apoptosis, indicating that its mod e of action only occurs through competitive inhibition of hPRL. We provide some molecular basis of this antagonistic effect by demonstrating that G129 R-hPRL competitively inhibits hPRL-activation of the JAK-STAT and MAPK path ways, two signaling cascades involved in the mitogenic effect of hPRL in ma mmary epithelial cells. This competitive inhibition persists for at least 4 8 h, as evidenced by long term analysis of STAT5b activation or of progress ion through cell cycle. These results are the first demonstration at the mo lecular level that hPRL antagonists interfering with receptor dimerization disrupt signaling events in breast cancer cells, which prevents hPRL-induce d cell proliferation.