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

Ciscar, Marina; Trinidad, Eva M.; Perez-Chacon, Gema; Alsaleem, Mansour; Jimenez, Maria; Jimenez-Santos, Maria J; Perez-Montoyo, Hector; Sanz-Moreno, Adrian; Vethencourt, Andrea; Toss, Michael; Petit, Anna; Soler-Monso, Maria T; Lopez, Victor; Gomez-Miragaya, Jorge; Gomez-Aleza, Clara; Dobrolecki, Lacey E.; Lewis, Michael T.; Bruna, Alejandra; Mouron, Silvana; Quintela-Fandino, Miguel; Al-Shahrour, Fatima; Martinez-Aranda, Antonio; Sierra, Angels; Green, Andrew R.; Rakha, Emad; Gonzalez-Suarez, Eva

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Authors

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

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Eva Gonzalez-Suarez



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.

Journal Article Type Article
Acceptance Date Feb 8, 2023
Online Publication Date Mar 7, 2023
Publication Date Mar 7, 2023
Deposit Date Mar 10, 2023
Publicly Available Date Apr 21, 2023
Journal EMBO Molecular Medicine
Print ISSN 1757-4676
Electronic ISSN 1757-4684
Peer Reviewed Peer Reviewed
Volume 15
Issue 4
Article Number e16715
DOI https://doi.org/10.15252/emmm.202216715
Keywords Breast cancer patient-derived xenografts; ER negative breast cancer; menopause; pharmacological RANKL inhibitors; RANK-RANKL
Public URL https://nottingham-repository.worktribe.com/output/18236709
Publisher URL https://www.embopress.org/doi/full/10.15252/emmm.202216715

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