title: Progesterone/RANKL is a major regulatory axis in the human breast.
abstract: Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor κB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR(+) breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention.
authors.affiliation: Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tanos
authors.forename: George
authors.initials: G
authors.lastname: Sflomos
authors.forename: Pablo C
authors.initials: PC
authors.lastname: Echeverria
authors.forename: Ayyakkannu
authors.initials: A
authors.lastname: Ayyanan
authors.forename: Maria
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Delaloye
authors.forename: Wassim
authors.initials: W
authors.lastname: Raffoul
authors.forename: Maryse
authors.initials: M
authors.lastname: Fiche
authors.forename: William
authors.initials: W
authors.lastname: Dougall
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Ozden
authors.initials: O
authors.lastname: Yalcin-Ozuysal
authors.forename: Cathrin
authors.initials: C
authors.lastname: Brisken
mesh_terms: D001940:Breast / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D011374:Progesterone / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism
chemical_list: D053245:RANK Ligand; D011980:Receptors, Progesterone; D011374:Progesterone