title: RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation.
abstract: RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormone-dependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. ©2016 AACR.
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Yoldi
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pellegrini
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Trinidad
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Cordero
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gomez-Miragaya
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology Lab, Catalan Institute of Oncology, IDIBELL, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Serra-Musach
authors.affiliation: Therapeutic Innovation Unit, Amgen Inc., Seattle, Washington.
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
authors.forename: Purificación
authors.initials: P
authors.lastname: Muñoz
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology Lab, Catalan Institute of Oncology, IDIBELL, Barcelona, Spain.
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: Centro Nacional de Biotecnología/CSIC, UAM Cantoblanco, Madrid, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Planelles
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. egsuarez@idibell.cat.
authors.forename: Eva
authors.initials: E
authors.lastname: González-Suárez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000067696:Ataxin-1 / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D043823:Taxoids / Q000494:pharmacology; D050656:Transcription Factor AP-2 / Q000502:physiology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C493677:TFAP2B protein, human; C505686:TNFRSF11A protein, human; D043823:Taxoids; D050656:Transcription Factor AP-2; D000077143:Docetaxel