Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk

• Published in: The journal of clinical endocrinology and metabolism Vol. 101; no. 11; pp. 4449 - 4460
• Main Authors: Chakhtoura, Zeina, Laki, Fatima, Bernadet, Marie, Cherifi, Ibtissem, Chiche, Aurélie, Pigat, Natascha, Bernichtein, Sophie, Courtillot, Carine, Boutillon, Florence, Bièche, Ivan, Vacher, Sophie, Tanguy, Marie-Laure, Bissery, Anne, Grouthier, Virginie, Camparo, Philippe, Foretz, Marc, Do Cruzeiro, Marcio, Pierre, Rémi, Rakotozafy, Fabienne, Tichet, Jean, Tejedor, Isabelle, Guidotti, Jacques-Emmanuel, Sigal-Zafrani, Brigitte, Goffin, Vincent, Touraine, Philippe
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.11.2016; Copyright by The Endocrine Society
• Subjects: Adolescent; Adult; Animal models; Animals; Breast cancer; Breast Neoplasms - genetics; Cohort Studies; Disease Models, Animal; Endocrinology; Female; Fibroadenoma; Fibroadenoma - genetics; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phenotypes; Population studies; Prolactin; Receptors, Prolactin - genetics; Transgenic mice; Tumorigenesis; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2016-2372

Context:In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLRI146L and PRLRI176V).Objective:This study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis.Design:This was an observational study and transgenic mouse model analysis.Setting:The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris.Patients or Other Participants:We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLRI146L or PRLRWT.Intervention:We aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer.Results:This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLRI146L exhibited very mild histological mammary phenotype but tumors were never observed.Conclusion:PRLRI146L and PRLRI176V variants are not associated with breast cancer or MFA risk. However, one cannot exclude that low but sustained PRLR signaling may facilitate or contribute to pathological development driven by oncogenic pathways. Long-term patient follow-up should help to address this issue.