RANK is a poor prognosis marker and a therapeutic target in ER‐negative postmenopausal breast cancer

Autor: Marina Ciscar, Eva M Trinidad, Gema Perez‐Chacon, Mansour Alsaleem, Maria Jimenez, Maria J Jimenez‐Santos, Hector Perez‐Montoyo, Adrian Sanz‐Moreno, Andrea Vethencourt, Michael Toss, Anna Petit, Maria T Soler‐Monso, Victor Lopez, Jorge Gomez‐Miragaya, Clara Gomez‐Aleza, Lacey E Dobrolecki, Michael T Lewis, Alejandra Bruna, Silvana Mouron, Miguel Quintela‐Fandino, Fatima Al‐Shahrour, Antonio Martinez‐Aranda, Angels Sierra, Andrew R Green, Emad Rakha, Eva Gonzalez‐Suarez
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 15, Iss 4, Pp 1-12 (2023)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202216715
Popis: 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 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.
Databáze: Directory of Open Access Journals
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