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Expression of receptor activator of NFkB (RANK) drives stemness and resistance to therapy in ER+HER2- breast cancer

2020; Impact Journals LLC; Volume: 11; Issue: 19 Linguagem: Inglês

10.18632/oncotarget.27576

1949-2553

Inês Gomes, Bernardo P. de Almeida, Sara Dâmaso, André Mansinho, Inês Correia, Sara Carolina Henriques, Raquel Cruz-Duarte, Guilherme Vilhais, Pedro M. Félix, Patrícia Alves, Patrícia Corredeira, Nuno L. Barbosa‐Morais, Luís Costa, Sandra Casimiro,

Cytokine Signaling Pathways and Interactions

// Inês Gomes 1 , Bernardo P. de Almeida 2 , 4 , Sara Dâmaso 3 , André Mansinho 1 , 3 , Inês Correia 1 , Sara Henriques 1 , Raquel Cruz-Duarte 1 , Guilherme Vilhais 1 , Pedro Félix 1 , Patrícia Alves 1 , Patrícia Corredeira 1 , Nuno L. Barbosa-Morais 2 , Luis Costa 1 , 3 and Sandra Casimiro 1 1 Luis Costa Laboratory, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal 2 Nuno Morais Laboratory, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal 3 Serviço de Oncologia, Hospital de Santa Maria-CHULN, Lisboa, Portugal 4 Current affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria Correspondence to: Sandra Casimiro, email: scasimiro@medicina.ulisboa.pt Keywords: RANKL-RANK pathway; ER+ breast cancer; resistance to chemo and hormone therapy; stemness; metastization Received: November 07, 2019 Accepted: April 10, 2020 Published: May 12, 2020 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.