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Impact de la signalisation constitutive du récepteur de la prolactine sur la physiopathologie mammaire

Abstract : The link between prolactin (PRL) and mammary tumorigenesis is supported by many experimental, clinical and epidemiologic data. However, mutations on the gene coding for PRL or its receptor (PRLR) have never been identified in the context of breast cancer. In 2008, our Laboratory identified the first gain-of-function polymorphism of the PRLR in patients presenting with a rare form of benign mammary tumors (mammary polyadenomatosis). Indeed, the one-residue substitution of isoleucine 146 by a leucine in the extracellular domain of the PRLR conferred a higher basal activity than that of the wild-type PRLR. Within the framework of my thesis, we have tried to determine the consequences of expressing a constitutively active PRLR in a healthy or cancerous mammary cell. With this aim, we have used two complementary approaches. On one hand, we generated two models of knock-in mice carrying only one copy of the mutated (I146L) or wild-type (as control) human PRLR. We then analyzed the mammary phenotypes of these mice at various ages. We did not observe any tumor development, indicating that the PRLR-I146L is not an oncogene. Nevertheless, the mammary glands of old mice presented certain histological anomalies suggesting a possible interference of the mutated PRLR with normal mammary differentiation. The analysis of these phenotypes must continue to determine their extent and the potential underlying mechanisms. On the other hand, we carried out an in vitro study using human breast cancer cell lines. A parallel study in the Laboratory had showed that the I146D substitution led to a stronger constitutive activity of the PRLR than the natural I146L polymorphism. Thus, we generated stable clones of two human breast cancer cell lines expressing the PRLR-I146D. In spite of its constitutive activity, the expression of PRLR-I146D did not result in any selective advantage for tumor cells in terms of proliferation, nor did it modify their histological phenotype (Zhang, Cherifi et al., in revision). In conclusion, our work has shown that the expression of a gain-of-function mutation in the PRLR is insufficient to transform a healthy mammary cell, or to enhance the proliferation of mammary cancer cells.
Keywords : Pathophysiology
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Submitted on : Tuesday, September 8, 2015 - 6:29:06 PM
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  • HAL Id : tel-01195990, version 1


Ibtissem Cherifi. Impact de la signalisation constitutive du récepteur de la prolactine sur la physiopathologie mammaire. Physiologie [q-bio.TO]. Université René Descartes - Paris V, 2014. Français. ⟨NNT : 2014PA05T061⟩. ⟨tel-01195990⟩



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