Casimiro, Sandra Cristina Cara de AnjoCosta, Luís António Marques daGomes, Inês Fernandes2024-05-242023-122023-09http://hdl.handle.net/10451/64865Despite the efficacy of local treatments to control early breast cancer (BC) and great advances in the development of target therapies, relapse and progression rates are still high, mostly due to (neo)adjuvant systemic therapy resistance. Therefore, it is extremely important to unravel drivers of therapeutic resistance and devise strategies to overcome it. The receptor activator of nuclear factor-kB (RANK)-RANK ligand (RANKL) signaling pathway is a key regulator of several physiopathological processes, including osteoclastogenesis, breast carcinogenesis and BC progression. In this work, we provide the first characterization of RANK overexpressing (RANK OE) luminal BC, including its effect in response to standard of care therapies. We found that RANK OE luminal BC is characterized by a staminal and mesenchymal phenotype and decreased proliferation rate. Moreover, RANK OE cells were more invasive and less sensitive to chemo, endocrine and cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) therapy. Additionally, we disclose the mechanism(s) involved in RANK-mediated resistance to CDK4/6i and demonstrate that the pharmacological inhibition of RANK-RANKL pathway may improve the efficacy of this class of drugs. Major RANK-associated intrinsic or acquired resistance drivers were the decreased proliferation rate and chronic interferon γ-response activation, characteristic of luminal RANK OE cells and tumors. Importantly, RANKL inhibitors (RANKLi) restored sensitivity and prevented acquired resistance to CDK4/6i. Stemming from these findings, we also demonstrate that the genetic or pharmacologic inhibition of RANK-pathway improves the response to CDK4/6i of Rb-proficient TNBC, where current therapeutic options are mostly limited to chemotherapy. Overall, our results advanced the current knowledge about the role of RANK pathway in BC, clearly implicated in luminal BC biology. Moreover, this work has a strong translational value, showing that the use of RANKLi may span far beyond its current use in the clinics as a bone target therapy, and be repurposed as a new add-on to CDK4/6i in the treatment of metastatic luminal and TNBC patients.engcancro da mama (CM)resistência à terapiavia de sinalização do recetor ativador do fator nuclear-kB (RANK)inibidores de cinases dependentes de ciclina 4 e 6 (iCDK4/6)inibidores do ligando do RANK (iRANKL)breast cancer (BC)therapy resistancereceptor activator of nuclear factor-kB (RANK) signaling pathwaycyclin dependent kinase 4 and 6 inhibitors (CDK4/6i)RANK ligand inhibitors (RANKLi)doctoral thesis101599617