RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.
Date
2023-04-11ICR Author
Author
Ciscar, M
Trinidad, EM
Perez-Chacon, G
Alsaleem, M
Jimenez, M
Jimenez-Santos, MJ
Perez-Montoyo, H
Sanz-Moreno, A
Vethencourt, A
Toss, M
Petit, A
Soler-Monso, MT
Lopez, V
Gomez-Miragaya, J
Gomez-Aleza, C
Dobrolecki, LE
Lewis, MT
Bruna, A
Mouron, S
Quintela-Fandino, M
Al-Shahrour, F
Martinez-Aranda, A
Sierra, A
Green, AR
Rakha, E
Gonzalez-Suarez, E
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
ER negative breast cancer
RANK-RANKL
breast cancer patient-derived xenografts
menopause
pharmacological RANKL inhibitors
Female
Humans
Breast Neoplasms
Denosumab
Receptor Activator of Nuclear Factor-kappa B
Postmenopause
RANK Ligand
Signal Transduction
Research team
Preclin Paed Cancer Evo
Language
eng
Date accepted
2023-02-08
License start date
2023-04-11
Citation
EMBO Molecular Medicine, 2023, 15 (4), pp. e16715 -
Publisher
WILEY