Publication Date

4-11-2023

Journal

EMBO Molecular Medicine

DOI

10.15252/emmm.202216715

PMID

36880458

PMCID

PMC10086586

PubMedCentral® Posted Date

3-7-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Female, Humans, Breast Neoplasms, Denosumab, Receptor Activator of Nuclear Factor-kappa B, Postmenopause, RANK Ligand, Signal Transduction, breast cancer patient‐derived xenografts, ER negative breast cancer, menopause, pharmacological RANKL inhibitors, RANK‐RANKL

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.

Comments

Associated Data

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.