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

Llovera, Marta; Pichard, C.; Bernichtein, Sophie; Jeay, Sébastien; Touraine, Philippe; Kelly, Paul A.; Goffin, Vincent

doi:10.1038/sj.onc.1203846

Cited by 93 publications

(89 citation statements)

References 49 publications

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“…Rather, we believe that the down regulation of the bcl-2 expression by hPRL-G129R is through the competitive inhibition of the effects induced by endogenous PRL. These findings are consistent with those of Llovera et al (2000), who have found that the hPRL-G129R does not activate any specific signaling molecules in their systems.…”

Section: Discussionsupporting

confidence: 82%

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

2002

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Section: Discussionsupporting

confidence: 82%

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

2002

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…Among other pathways, PRL activates the extracellular signal-regulated kinase (ERK) and STAT signaling pathways, with STAT5a being the principal STAT isoform involved in its mammary effects (Campbell et al, 1994;Rui et al, 1994;Liu et al, 1997;Clevenger and Kline, 2001). 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).…”

Section: Introductionmentioning

confidence: 99%

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

Huang

Jiang

et al. 2006

Oncogene

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Prolactin (PRL) is a polypeptide hormone produced by the anterior pituitary gland and other sites that acts both systemically and locally to cause lactation and other biological effects by interacting with the PRL receptor, a Janus kinase (JAK)2-coupled cytokine receptor family member, and activating downstream signal pathways. Recent evidence suggests PRL is a player in the pathogenesis and progression of breast cancer. Epidermal growth factor (EGF) also has effects on breast tissue, working through its receptors, epidermal growth factor receptor (EGFR) and ErbB-2 (c-neu, HER2), both intrinsic tyrosine kinase growth factor receptors. EGFR promotes pubertal breast ductal morphogenesis in mice, and both EGFR and ErbB-2 are relevant in pathogenesis and behavior of breast and other human cancers. Previous studies showed that PRL and EGF synergize to enhance motility in the human breast cancer cell line, T47D. In this study, we explored crosstalk between the PRL and EGF signaling pathways in T47D cells, with an ultimate aim of understanding how these two important factors might work together in vivo to affect breast cancer behavior. Both PRL and EGF caused robust signaling in T47D cells; PRL acutely activated JAK2, signal transducer and activator of transcription-5 (STAT5), and extracellular signal-regulated kinase-1 and -2 (ERK1 and ERK2), whereas EGF caused EGFR activation and consequent src homology collagen (SHC) activation and ERK activation. Notably, PRL also caused phosphorylation of the EGFR and ErbB-2 at sites detected by PTP101, an antibody that recognizes threonine phosphorylation at consensus motifs for ERK-induced phosphorylation. PRL-induced PTP101-reactive phosphorylation was prevented by pretreatment with PD98059, an ERK pathway inhibitor. Furthermore, PRL synergized with EGF in activating SHC and ERK and transactivating a luciferase reporter driven by c-fos gene enhancer elements, suggesting that PRL allowed markedly enhanced EGF signaling. This was accompanied by substantial inhibition of EGF-induced EGFR downregulation when PRL and EGF cotreatment was compared to EGF treatment alone. This effect of PRL was abrogated by ERK pathway inhibitor pretreatment. Our data suggest that PRL synergistically augments EGF signaling in T47D breast cancer cells at least in part by lessening EGF-induced EGFR downregulation and that this effect requires PRL-induced ERK activity and threonine phosphorylation of EGFR.

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“…Cells were solubilized in 1 ml of lysis buffer (30 min rotation at 4°C; Ref. 34), and lysates were centrifuged for 10 min at 13,000 ϫ g, and then the protein content of supernatants was measured by the Bradford assay.…”

Section: Cell-based Bioassaysmentioning

confidence: 99%

“…The prototype of such mutations is the substitution of the conserved helix 3 glycine for larger side chain residues, such as arginine or tryptophan, which sterically hinder the binding site 2 (30,31). So-called G120R-hGH or G129R-hPRL analogs were found to be potent antagonists of their respective receptors in many in vitro bioassays (30,32), including proliferation and PRL receptor-mediated activation of signaling cascades in human breast cancer cell lines in vitro (33)(34)(35). In human mammary tumor cell lines, the PRLR antagonist G129R-hPRL was also reported to induce apoptosis (35,36), to inhibit PRL activation of transcription factor STAT3 (37), and to reduce tumor growth in vivo (38).…”

mentioning

confidence: 99%

Development of Pure Prolactin Receptor Antagonists

Bernichtein

Kayser

Dillner

et al. 2003

Journal of Biological Chemistry

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113

133

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Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all forms of PRL receptor antagonists obtained to date exhibit partial agonism, preventing their therapeutic use as full antagonists. In the present study, we describe the development of new human PRL antagonists devoid of agonistic properties and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including highly sensitive assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as assessed by analyzing their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland, and prostate). Finally, by using transgenic mice expressing PRL specifically in the prostate, which exhibit constitutively activated signaling cascades paralleling hyperplasia, we show that these new PRL analogs are able to completely revert PRL-activated events. These second generation human PRL antagonists are good candidates to be used as inhibitors of growth-promoting actions of PRL.

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

Cited by 93 publications

References 49 publications

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

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

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

Development of Pure Prolactin Receptor Antagonists

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