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
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Laudine Communal1, Myriam Vilasco1,*, Justine Hugon-Rodin1,2,*, Aurélie Courtin1, Najat Mourra3, Najiba Lahlou4, Morwenna Le Guillou5, Muriel Perrault de Jotemps6, Marie-Pierre Chauvet7, Marc Chaouat8, Pascal Pujol9, Jean Feunteun5, Suzette Delaloge10, Patricia Forgez1, Anne Gompel1,2
1UMRS 1007, Saints Pères, Paris Descartes University, Paris, France
2UF de Gynécologie-Endocrinienne, Paris Descartes University, AP-HP, Hôpital Cochin, Paris, France
3Service d’Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Saint-Antoine, Paris, France
4Service de Biologie Hormonale, Paris Descartes University, AP-HP, Hôpital Cochin, Paris, France
5CNRS UMR8200 Gustave Roussy, Stabilité génétique et Oncogénèse, Paris-Saclay University, Villejuif, France
6Service de Chirurgie Plastique et Reconstructrice, Clinique Hartmann, Neuilly sur Seine, France
7Département de Sénologie, Centre Oscar Lambret, Lille, France
8Service de Chirurgie Plastique Reconstructrice et Esthétique et Chirurgie des Brûlés, Denis Diderot University, AP-HP, Hôpital Saint-Louis, Paris
9Centre Hospitalier Universitaire, Montpellier University, Montpellier, France
10Breast Cancer Group, Gustave Roussy Cancer Campus, Villejuif, France
*These authors have contributed equally to this work
Patricia Forgez, email: [email protected]
Anne Gompel, email: [email protected]
Keywords: BRCA1, breast cancer, ovarian hormones, prevention, ulipristal acetate
Received: January 25, 2016 Accepted: May 09, 2016 Published: May 26, 2016
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.
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