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This version published online on November 6, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-1494
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Submitted on July 13, 2009
Accepted on October 6, 2009

Characterization of Two Constitutively Active Prolactin Receptor Variants in a Cohort of 95 Women with Multiple Breast Fibroadenomas

Carine Courtillot, Zeina Chakhtoura, Roman Bogorad, Catherine Genestie, Sophie Bernichtein, Yasmina Badachi, Gilbert Janaud, Jean-Pierre Akakpo, Anne Bachelot, Frédérique Kuttenn, Vincent Goffin, Philippe Touraine*, and on behalf of the Benign Breast Diseases Study Group

Département d'Endocrinologie et Médecine de la Reproduction, Centre des Maladies Rares Gynécologiques (C.C., Z.C., A.B., F.K., P.T.), and Départements de Radiologie (Y.B., G.J., J.-P.A.) and d'Anatomopathologie (C.G.), Assistance Publique-Hôpitaux de Paris, GH Pitié Salpêtrière, F-75651 Paris Cedex 13, France; Institut National de la Santé et de la Recherche Médicale Unité 845 (C.C., Z.C., R.B., S.B., A.B., F.K., V.G., P.T.), Centre de Recherche Croissance et Signalisation, Equipe "Prl, GH et tumeurs," F-75015 Paris, France; Faculté de Médecine (R.B., S.B., F.K., V.G.), Université Paris Descartes, site Necker, F-75015 Paris, France; and Faculté de Médecine (A.B., P.T.), Université Pierre et Marie Curie, site Pitié-Salpêtrière, Paris F-75013, France

* To whom correspondence should be addressed. E-mail: philippe.touraine{at}psl.aphp.fr.

Background: The role of prolactin (PRL) and its receptor (hPRLR) in promoting breast tumors is debated. We recently identified a gain-of-function hPRLR variant (I146L) in four women with multiple breast fibroadenomas (MFA) and no control subject.

Objectives: The specific aims were to describe this cohort of women presenting with MFA to identify and functionally characterize germline variants of hPRL/hPRLR genes and compare phenotypes of all patients.

Design: Ninety-five patients prospectively underwent clinical examination, breast ultrasonography, magnetic resonance imaging, and hormonal evaluation of gonadal and lactotrope functions. We analyzed hPRL/hPRLR coding sequences and made comparisons with a control population of 194 women. Functional characterization of hPRLR variants was performed. Pathology and immunochemistry were systematically carried out after surgical removal of tumors.

Results: One third of patients had a family history of breast disease. No hormonal imbalance was observed, except 30.7% of explosive stimulated PRL. Prolactin receptor variants were identified in exon 5 (I76V: 10 patients, eight controls) and exon 10 (one patient, no control). Both I146L and I76V variants exhibited constitutive activity. Pathology showed common fibroadenomas and identified six benign phyllodes tumors. Estrogen and progesterone receptors were detected in 85 and 98% of samples, respectively. Ki-67 median staining was less than 5%. No phenotypic difference was observed between carriers and noncarriers of either hPRLR variant.

Conclusion: We present the largest population with MFA ever described, 15% of which had a hPRLR exhibiting basal activity in vitro. This questions the involvement of the hPRLR in MFA etiology and the potential relevance of therapeutic inhibition of PRLR signaling in patients.






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