Prolactin involvement in breast cancer.

Abstract

Normal development and differentiation of the mammary gland are profoundly influenced by prolactin (PRL). In rodent mammary cancer PRL plays a well defined role, but its role in human breast cancer has not been appreciated until recently. It is now clear that breast tissue, both normal and malignant, is a significant source of extrapituitary PRL. Thus an autocrine/paracrine role of PRL in human breast cancer may be invoked. Both PRL and PRL receptor mRNA are expressed in the vast majority of breast cancer biopsies independent of estrogen and progesterone receptor status. An autocrine/ paracrine PRL acting in human breast cancer requires that this hormone's action be blocked at the cellular level, as opposed to suppressing the synthesis and secretion of pituitary PRL. Mutants of PRL or human growth hormone are being explored which act as selective PRL antagonists. In addition, tamoxifen has been shown to act locally at the target tissue by binding directly to the PRL receptor and thus inhibiting PRL's action. These strategies may have clinical relevance in treating PRL- Endocrine-Related Cancer (1999) 6 389-404 responsive human breast cancer.

Clinicopathological significance of prolactin receptor expression in colorectal carcinoma and corresponding metastases

“…Data obtained from breast cancer cell lines and in vivo models show that intracellular signaling involves phosphorylation of cytoplasmatic transcription factors, eg, signal transducer and activator of transcription (STAT) 1, STAT3, or STAT5, through recruited kinases, eg, janus-kinase JAK2, or activation of the ras-MAPK pathway. 12,14 According to our data, prolactin receptor is widely expressed in colorectal cancer. Immunoreactivity was significantly associated with tumor differentiation and histological subtype, which is reported in this study for the first time.…”

“…On prolactin binding, the receptor exerts mitogenic effects involving various intracellular signaling cascades, such as JAK-STAT, ras-MAPK, and SHCGrb pathways. [12][13][14] Thus, prolactin and its receptor are promising therapeutic targets, wherein prolactin receptor antagonism appears to be the most promising interventional approach. [15][16][17] The significance of prolactin and its receptor in colorectal cancer, however, is largely unknown.…”

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).…”

“…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).…”

Regulation of bcl-2 gene expression in human breast cancer cells by prolactin and its antagonist, hPRL-G129R

“…Controversy, however, still exists regarding the role of hPRL in human breast cancer. Emerging evidence links hPRL to human breast cancer including: (a) the detection of biologically active hPRL in human breast cancer cells, which suggests that hPRL is produced locally as an autocrine/paracrine growth factor within the mammary gland (Clevenger et al, 1995;Ginsburg and Vonderhaar, 1995;Goffin et al, 1996, Goffin andVonderhaar, 1999); (b) PRL receptor (PRLR) levels are significantly higher in human breast cancer cells than in normal breast epithelial cells (Kelly et al, 1991); (c) transgenic mice over expressing hPRL have a higher breast cancer incidence (Wennbo et al, 1997) and (d) the hPRL antagonist, hPRL-G129R, slows the growth rate of human breast cancer xymographs in nude mice (Chen et al, 2002). These examples support hPRL's role as a mitogen in human breast cancer and suggest that its antagonist may have potential in treating human breast cancer.…”