The role of RANKL/RANK pathway on ER+ breast cancer’s tumorigenesis and resistance to therapy

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2021O cancro da mama é o segundo cancro mais frequente a nível mundial, sendo responsável por mais de 600,000 mortes por ano. Os subtipos recetores hormonais positivos (RH+) representam a vasta maioria dos casos, estando associados a um melhor prognóstico. No entanto, e apesar de todos os avanços terapêuticos, 30% dos cancros da mama RH+ continuam a progredir para doença metastática. Ao longo das últimas duas décadas, a via RANKL/RANK emergiu como uma importante via de sinalização em vários mecanismos além da homeostase óssea, nos quais se incluem a iniciação e progressão metastática do cancro da mama. Neste trabalho revemos e resumimos a escassa literatura disponível acerca do papel fisiopatológico desta via na carcinogénese mamária luminal e do seu potencial papel na resistência à hormono- e quimioterapia, complementando a informação existente com dados experimentais obtidos pelo nosso grupo. Abordamos ainda a evidência disponível acerca do potencial benefício de inibir a via RANKL/RANK com o objetivo de melhorar os outcomes clínicos deste tipo de tumor, descrevendo e discutindo detalhadamente os resultados contraditórios de dois ensaios clínicos de fase 3 recentemente publicados, o ABCSG-18 e o D-CARE, que se debruçaram sobre os efeitos modificadores de doença do denosumab, um anticorpo monoclonal anti-RANKL, como terapêutica adjuvante em cancro da mama precoce. Concluímos que, apesar da inúmera evidência que sugere que a via RANKL/RANK pode assumir um importante papel na resistência intrínseca e progressão sob terapêutica em cancro da mama, não há atualmente evidência clara que justifique a recomendação de denosumab com o intuito de modificar a sobrevida dos doentes com cancro da mama luminal. No entanto, não descartamos que tal possa vir a acontecer no futuro, sendo para isso necessários mais estudos clínicos com vista a selecionar a população de doentes com maior probabilidade de beneficiar desta intervenção.Breast cancer is the second most common cancer worldwide and is responsible for over 600,000 deaths per year. Hormone-receptor (HR) + subtypes represent the vast majority of cases and are associated with better prognoses. However, and despite all therapeutic achievements, 30% of HR+ breast cancers still progress to metastatic disease, highlighting the opportunity to further improve Luminal breast cancer outcomes. Over the last two decades, RANKL/RANK pathway emerged as a critical signaling pathway involved in several mechanisms beyond bone homeostasis, including breast cancer initiation and metastatic progression, where it is thought to contribute to resistance to therapy that ultimately leads to disease progression and death. In this work, we review and summarize the scarce literature regarding the pathophysiological role of this pathway on Luminal breast tumorigenesis and its potential role on the resistance to standard of care endocrine and chemotherapy, while complementing it with experimental data obtained by our group. We also address the potential benefit of using RANKL/RANK inhibition as a way to improve Luminal breast cancer diseaserelated outcomes, extensively describing and discussing the contradictory results of ABCSG-18 and D-CARE, two recently published phase 3 clinical trials that studied the disease-modifying effects of RANKL inhibition with monoclonal antibody denosumab in early breast cancer’s adjuvant setting. We conclude that, despite the innumerous evidence that suggests that RANKL/RANK pathway may assume an important role on the intrinsic resistance and progression under therapy of human breast cancer, current evidence is not enough to recommend adjuvant denosumab with the intent of improving disease-related outcomes in any setting. However, we do not discard that this may change in the future, which is why we encourage further clinical studies to access the true benefit of using denosumab on a selected cohort of Luminal breast cancer patients that seem more likely to benefit from this intervention

The roadmap of RANKL/RANK pathway in cancer

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.This work was supported by the research project PTDC/MED-ONC/28636/2017 from Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado. IG is supported by the FCT PhD grant SFRH/BD/139178/2018.info:eu-repo/semantics/publishedVersio

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

© Gomes et al. Copyright: Gomes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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.This project was funded by the research project PTDC/MED-ONC/28636/2017 from Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado. IG is supported by the FCT PhD grant SFRH/BD/139178/2018info:eu-repo/semantics/publishedVersio

Primary CDK4/6 inhibitor and endocrine therapy in locally advanced breast cancer and its effect on gut and intratumoral microbiota : case report

Copyright © 2024 Vilhais, Alpuim Costa, Fontes-Sousa, Ribeiro, Martinho, Botelho de Sousa, Santos, Negreiros, Canastra, Borralho, Guia Pereira, Marçal, Germano Sousa, Chaleira, Rocha, Calhau and Faria. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Locally advanced breast cancer poses significant challenges to the multidisciplinary team, in particular with hormone receptor (HR) positive, HER2-negative tumors that classically yield lower pathological complete responses with chemotherapy. The increasingly significant use of CDK 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) in different breast cancer settings has led to clinical trials focusing on this strategy as a primary treatment, with promising results. The impact of the microbiota on cancer, and vice-versa, is an emerging topic in oncology. The authors report a clinical case of a postmenopausal female patient with an invasive breast carcinoma of the right breast, Luminal B-like, staged as cT4cN3M0 (IIIB). Since the lesion was considered primarily inoperable, the patient started letrozole and ribociclib. Following 6 months of systemic therapy, the clinical response was significant, and surgery with curative intent was performed. The final staging was ypT3ypN2aM0, R1, and the patient started adjuvant letrozole and radiotherapy. This case provides important insights on primary CDK4/6i plus ET in locally advanced unresectable HR+/HER2- breast cancer and its potential implications in disease management further ahead. The patient's gut microbiota was analyzed throughout the disease course and therapeutic approach, evidencing a shift in gut microbial dominance from Firmicutes to Bacteroidetes and a loss of microbial diversity following 6 months of systemic therapy. The analysis of the intratumoral microbiota from the surgical specimen revealed high microbial dissimilarity between the residual tumor and respective margins.info:eu-repo/semantics/publishedVersio