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oai:repisalud.isciii.es:20.500.12105/251722025-12-18T13:01:37Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571

00925njm 22002777a 4500 dc Ciscar, Marina author Trinidad, Eva M author Perez-Chacon, Gema author Alsaleem, Mansour author Jimenez, Maria author Jimenez-Santos, Maria J author Perez-Montoyo, Hector author Sanz-Moreno, Adrian author Vethencourt, Andrea author Toss, Michael author Petit, Anna author Soler-Monso, Maria T author Lopez, Victor author Gomez-Miragaya, Jorge author Gomez-Aleza, Clara author Dobrolecki, Lacey E author Lewis, Michael T author Bruna, Alejandra author Mouron, Silvana author Al-Shahrour, Fatima author Quintela Fandino, Miguel Angel author Martinez-Aranda, Antonio author Sierra, Angels author Green, Andrew R author Rakha, Emad author Gonzalez-Suarez, Eva author Ciscar, Marina author Trinidad, Eva M author Perez-Chacon, Gema author Alsaleem, Mansour author Jimenez, Maria author Jimenez-Santos, Maria J author Perez-Montoyo, Hector author Sanz-Moreno, Adrian author Vethencourt, Andrea author Toss, Michael author Petit, Anna author Soler-Monso, Maria T author Lopez, Victor author Gomez-Miragaya, Jorge author Gomez-Aleza, Clara author Dobrolecki, Lacey E author Lewis, Michael T author Bruna, Alejandra author Mouron, Silvana author Martinez-Aranda, Antonio author Sierra, Angels author Green, Andrew R author Rakha, Emad author Gonzalez-Suarez, Eva author 2023-04-11 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 protein expression is an independent biomarker of poor prognosis in postmenopausal and ER 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. EMBO Mol Med . 2023 Apr 11;15(4):e16715. Embo Molecular Medicine 36880458 https://hdl.handle.net/20.500.12105/25172 ER negative breast cancer RANK-RANKL breast cancer patient-derived xenografts menopause pharmacological RANKL inhibitors RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.