@article { , title = {RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer}, abstract = {Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER−) from four independent cohorts. RANK protein expression was more frequent in ER− tumors, where it associated with poor outcome and poor response to chemotherapy. In ER− breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK proteinexpression is an independent biomarker of poor prognosis in postmenopausal andER− breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER− tumors after menopause.}, doi = {10.15252/emmm.202216715}, eissn = {1757-4684}, issn = {1757-4676}, issue = {4}, journal = {EMBO Molecular Medicine}, publicationstatus = {Published}, url = {https://nottingham-repository.worktribe.com/output/18236709}, volume = {15}, keyword = {Nottingham Breast Cancer Research Centre, Breast cancer patient-derived xenografts, ER negative breast cancer, menopause, pharmacological RANKL inhibitors, RANK-RANKL}, year = {2023}, author = {Ciscar, Marina and Trinidad, Eva M. and Perez-Chacon, Gema and Alsaleem, Mansour and Jimenez, Maria and Jimenez-Santos, Maria J and Perez-Montoyo, Hector and Sanz-Moreno, Adrian and Vethencourt, Andrea and Toss, Michael and Petit, Anna and Soler-Monso, Maria T and Lopez, Victor and Gomez-Miragaya, Jorge and Gomez-Aleza, Clara and Dobrolecki, Lacey E. and Lewis, Michael T. and Bruna, Alejandra and Mouron, Silvana and Quintela-Fandino, Miguel and Al-Shahrour, Fatima and Martinez-Aranda, Antonio and Sierra, Angels and Green, Andrew R. and Rakha, Emad and Gonzalez-Suarez, Eva} }