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

Oncogene volume 19, pages 4695–4705 (2000)Cite this article

Abstract

The involvement of human prolactin (hPRL) in breast cancer has been recently reconsidered based on its autocrine/paracrine proliferative effect described in human mammary tumor epithelial cells. Therefore, there is growing interest in the development of potent hPRL antagonists that may inhibit this effect. We previously designed hPRL analogs displaying antagonistic properties in a human transcriptional bioassay. We now report that the most potent of those analogs, G129R-hPRL, antagonizes all hPRL-induced effects analysed in various breast cancer cell lines, including cell proliferation. The analog per se lacks intrinsic agonistic activity on PRL receptor-activated signaling cascades, cell proliferation and apoptosis, indicating that its mode of action only occurs through competitive inhibition of hPRL. We provide some molecular basis of this antagonistic effect by demonstrating that G129R-hPRL competitively inhibits hPRL-activation of the JAK-STAT and MAPK pathways, two signaling cascades involved in the mitogenic effect of hPRL in mammary epithelial cells. This competitive inhibition persists for at least 48 h, as evidenced by long term analysis of STAT5b activation or of progression through cell cycle. These results are the first demonstration at the molecular level that hPRL antagonists interfering with receptor dimerization disrupt signaling events in breast cancer cells, which prevents hPRL-induced cell proliferation.

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Acknowledgements

The authors are grateful to Drs B Vonderhaar, C Mallet and M Norman for providing the breast cancer cell lines used in this work, and to Dr JA Martial for giving hPRL and G129R-hPRL expression plasmids. They also thank Dr E Baixeras and Dr M Lenoir for helpful discussions, and C Coridun for secretarial assistance. M Llovera is recipient of an EMBO fellowship and S Bernichtein is supported by the Minister of Research and Technology. This work was funded in part by INSERM, the ‘Association pour la Recherche sur le Cancer (ARC)’ and the ‘Ligue Nationale contre le Cancer’.

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  1. INSERM Unit 344, Molecular Endocrinology, Faculté de Médecine Necker, 156 rue de Vaugirard, Paris, 75730, Cedex 15, France

    Marta Llovera, Caroline Pichard, Sophie Bernichtein, Sébastien Jeay, Philippe Touraine, Paul A Kelly & Vincent Goffin

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Llovera, M., Pichard, C., Bernichtein, S. et al. Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation. Oncogene 19, 4695–4705 (2000). https://doi.org/10.1038/sj.onc.1203846

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