The Role of Prolactin in Mammary Carcinoma

Abstract

The contribution of prolactin (PRL) to the pathogenesis and progression of human breast cancer at the cellular, transgenic, and epidemiological levels is increasingly appreciated. Acting at the endocrine and autocrine/paracrine levels, PRL functions to stimulate the growth and motility of human breast cancer cells. The actions of this ligand are mediated by at least six recognized PRL receptor isoforms found on, or secreted by, human breast epithelium. The PRL/PRL receptor complex associates with and activates several signaling networks that are shared with other members of the cytokine receptor superfamily. Coupled with the recently identified intranuclear function of PRL, these networks are integrated into the in vitro and in vivo actions induced by ligand. These findings indicate that antagonists of PRL/PRL receptor interaction or PRL receptor-associated signal transduction may be of considerable utility in the treatment of human breast cancer.

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…A substantial literature suggests a role for PRL, possibly produced locally, in human cancers, including breast cancer (Goffin et al, 1999;Vonderhaar, 1999;Ben-Jonathan et al, 2002;Clevenger et al, 2003). Although clinical trials with dopamine agonists to reduce circulating PRL in women with breast cancer have not succeeded (Bonneterre et al, 1988;Anderson et al, 1993;McMurray et al, 1995), some epidemiologic data suggest correlation between increased serum PRL levels and breast cancer risk in postmenopausal women (Hankinson et al, 1999).…”

“…In mice, transgenic overexpression of PRL results in mammary tumor formation (Wennbo et al, 1997) and T47D breast cancer cells xenografted into nude mice respond in vivo to PRL with increased tumor growth (Chen et al, 2002). The mechanisms of PRL's influence on breast cancer behavior are incompletely understood and could be several (Schroeder et al, 2002;Clevenger et al, 2003;Gutzman et al, 2004Gutzman et al, , 2005; however, given the importance of EGFR and PRL on this form of cancer, we are intrigued by the implications of our data on PRL's ability to augment EGF signaling in T47D cells. Importantly, for our current work with T47D cells, previous studies with this cell line have established that PRL and EGF can cooperate with regard to cell migration and gene activation (Haraguchi et al, 1997;Maus et al, 1999).…”

“…Thus, our data also suggest the novel hypothesis that effects of PRL (and possibly other ERK-activating cytokines) on breast cancer cells could in part be related to modulation of EGF signaling by alteration of EGFR trafficking. As both PRL and EGF are potentially manipulatable targets in breast cancer (Nicholson et al, 2001;Chen et al, 2002;Clevenger et al, 2003;Lichtner, 2003;Harari, 2004;Laskin and Sandler, 2004;Goffin et al, 2005), this hypothesis is worthy of further testing in both cellular reconstitution systems and in vivo models.…”

“…PRL stimulates normal mammary growth, development and lactation, but also affects other reproductive aspects,such as osmoregulation, stress and behavior (Horseman, 1999;Rui, 2000;Hovey et al, 2001;Goffin et al, 2002;Grimm et al, 2002). Although controversial, the contribution of PRL to the pathogenesis and progression of human breast cancer is increasingly appreciated (Hankinson et al, 1999;Vonderhaar, 1999;Llovera et al, 2000b;Ben-Jonathan et al, 2002;Clevenger et al, 2003). PRL signals via the PRL receptor (PRLR), a cytokine receptor family member, which possesses no intrinsic tyrosine kinase activity and couples to the nonreceptor tyrosine kinase, Janus kinase (JAK)2 (Bazan, 1990;Argetsinger et al, 1993;Campbell et al, 1994;Rui et al, 1994;Bole-Feysot et al, 1998).…”

“…PRL induces ERK activity in several breast cancer cell lines, which may be important in PRL-induced biological effects in these cells (Das and Vonderhaar, 1996a, b;Llovera et al, 2000a;Schroeder et al, 2002;Acosta et al, 2003). In some cases, PRL synergizes with other growth factors in activating ERK (Clevenger et al, 2003).…”