title: Proliferation and ovarian hormone signaling are impaired in normal breast tissues from women with BRCA1 mutations: benefit of a progesterone receptor modulator treatment as a breast cancer preventive strategy in women with inherited BRCA1 mutations.
abstract: Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy.
authors.affiliation: UMRS 1007, Saints Pères, Paris Descartes University, Paris, France.
authors.forename: Laudine
authors.initials: L
authors.lastname: Communal
authors.affiliation: UMRS 1007, Saints Pères, Paris Descartes University, Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Vilasco
authors.affiliation: UMRS 1007, Saints Pères, Paris Descartes University, Paris, France.|UF de Gynécologie-Endocrinienne, Paris Descartes University, AP-HP, Hôpital Cochin, Paris, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Hugon-Rodin
authors.affiliation: UMRS 1007, Saints Pères, Paris Descartes University, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Courtin
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Saint-Antoine, Paris, France.
authors.forename: Najat
authors.initials: N
authors.lastname: Mourra
authors.affiliation: Service de Biologie Hormonale, Paris Descartes University, AP-HP, Hôpital Cochin, Paris, France.
authors.forename: Najiba
authors.initials: N
authors.lastname: Lahlou
authors.affiliation: CNRS UMR8200 Gustave Roussy, Stabilité génétique et Oncogénèse, Paris-Saclay University, Villejuif, France.
authors.forename: Morwenna
authors.initials: M
authors.lastname: Le Guillou
authors.affiliation: Service de Chirurgie Plastique et Reconstructrice, Clinique Hartmann, Neuilly sur Seine, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Perrault de Jotemps
authors.affiliation: Département de Sénologie, Centre Oscar Lambret, Lille, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Chauvet
authors.affiliation: Service de Chirurgie Plastique Reconstructrice et Esthétique et Chirurgie des Brûlés, Denis Diderot University, AP-HP, Hôpital Saint-Louis, Paris.
authors.forename: Marc
authors.initials: M
authors.lastname: Chaouat
authors.affiliation: Centre Hospitalier Universitaire, Montpellier University, Montpellier, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pujol
authors.affiliation: CNRS UMR8200 Gustave Roussy, Stabilité génétique et Oncogénèse, Paris-Saclay University, Villejuif, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Feunteun
authors.affiliation: Breast Cancer Group, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: UMRS 1007, Saints Pères, Paris Descartes University, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Forgez
authors.affiliation: UMRS 1007, Saints Pères, Paris Descartes University, Paris, France.|UF de Gynécologie-Endocrinienne, Paris Descartes University, AP-HP, Hôpital Cochin, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
mesh_terms: D000328:Adult; D000818:Animals; D001940:Breast / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009649:Norpregnadienes / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D009649:Norpregnadienes; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol; C555622:ulipristal acetate
keywords: BRCA1; breast cancer; ovarian hormones; prevention; ulipristal acetate