title: Characterization of two constitutively active prolactin receptor variants in a cohort of 95 women with multiple breast fibroadenomas.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Département d'Endocrinologie et Médecine de la Reproduction, Centre des Maladies Rares Gynécologiques, Assistance Publique-Hôpitaux de Paris, GH Pitié Salpêtrière, F-75651 Paris Cedex 13, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Courtillot
authors.forename: Zeina
authors.initials: Z
authors.lastname: Chakhtoura
authors.forename: Roman
authors.initials: R
authors.lastname: Bogorad
authors.forename: Catherine
authors.initials: C
authors.lastname: Genestie
authors.forename: Sophie
authors.initials: S
authors.lastname: Bernichtein
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Badachi
authors.forename: Gilbert
authors.initials: G
authors.lastname: Janaud
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Akakpo
authors.forename: Anne
authors.initials: A
authors.lastname: Bachelot
authors.forename: Frédérique
authors.initials: F
authors.lastname: Kuttenn
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.forename: Philippe
authors.initials: P
authors.lastname: Touraine
mesh_terms: D000293:Adolescent; D000328:Adult; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D018226:Fibroadenoma / Q000000981:diagnostic imaging / Q000235:genetics*; D005787:Gene Frequency; D018095:Germ-Line Mutation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011388:Prolactin / Q000235:genetics; D011859:Radiography; D011981:Receptors, Prolactin / Q000235:genetics* / Q000502:physiology; D046888:Tissue Array Analysis; D015533:Transcriptional Activation / Q000235:genetics; D014463:Ultrasonography; D055815:Young Adult
chemical_list: D050505:Mutant Proteins; D011981:Receptors, Prolactin; D011388:Prolactin