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

Abstract

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 (PRLR_I146L and PRLR_I176V).

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 PRLR_I146L or PRLR_WT.

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 PRLR_I146L exhibited very mild histological mammary phenotype but tumors were never observed.

Conclusion: PRLR_I146L and PRLR_I176V 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.