Abstract
The role of RANKL-RANK pathway in progesterone-driven mammary carcinogenesis and triple negative breast cancer tumorigenesis has been well characterized. However, and despite evidences of the existence of RANK-positive hormone receptor (HR)-positive breast tumors, the implication of RANK expression in HR-positive breast cancers has not been addressed before. Here, we report that RANK pathway affects the expression of cell cycle regulators and decreases sensitivity to fulvestrant of estrogen receptor (ER)-positive (ER+)/HER2- breast cancer cells, MCF-7 and T47D. Moreover, RANK overexpressing cells had a staminal and mesenchymal phenotype, with decreased proliferation rate and decreased susceptibility to chemotherapy, but were more invasive in vivo. In silico analysis of the transcriptome of human breast tumors, confirmed the association between RANK expression and stem cell and mesenchymal markers in ER+HER2- tumors. Importantly, exposure of ER+HER2- cells to continuous RANK pathway activation by exogenous RANKL, in vitro and in vivo, induced a negative feedback effect, independent of RANK levels, leading to the downregulation of HR and increased resistance to hormone therapy. These results suggest that ER+HER2- RANK-positive cells may constitute an important reservoir of slow cycling, therapy-resistance cancer cells; and that RANK pathway activation is deleterious in all ER+HER2- breast cancer cells, independently of RANK levels.
Highlights
Breast cancer is responsible for over 600,000 deaths per year worldwide [1], the vast majority due to cancer spread into distant organs
Since RANK-downstream effectors were activated in MCF7 and T47D parental cells, which express low levels of RANK, we confirmed that protein phosphorylation was RANK-dependent by analyzing p65 phosphorylation in Michigan Cancer Foundation-7 (MCF-7) parental and RANK RANK overexpression (OE) cells, in the presence of receptor activator of nuclear factor-kB ligand (RANKL) neutralized or not with MAB626, a RANKLspecific antibody (Supplementary Figure 1A)
In this study we demonstrate that as previously described for triple negative breast cancer (TNBC), RANK overexpressing (RANK OE) in estrogen receptor (ER)+HER2- cell lines induced the acquisition of mesenchymal traits, suggesting a more invasive behavior; and the onset of a stem celllike population
Summary
Breast cancer is responsible for over 600,000 deaths per year worldwide [1], the vast majority due to cancer spread into distant organs. The receptor activator of nuclear factor-kB ligand (RANKL)-RANK pathway was first identified as mediator of T and dendritic cells interaction [4], but it is mostly known for its role as key regulator of bone remodeling [5] and pathophysiology of bone metastases [6]. RANK is a member of the tumor necrosis factor receptor (TNFR) superfamily which is activated upon RANKL binding, promoting cell proliferation, survival and differentiation [7, 8]. The RANKL-RANK pathway emerged as a major mediator of hormone-driven breast carcinogenesis. RANKL is expressed downstream of activated progesterone receptor (PR) in HR-positive mammary epithelial cells (MECs), and drives the proliferation of www.oncotarget.com
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
