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Quimiorresistência induzida por sobreexpressão de RANK em cancro da mama do sub-tipo luminal
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Resumo(s)
O cancro da mama constitui globalmente não só uma das formas mais comuns de cancro, como tem elevada mortalidade associada. O desenvolvimento de terapêuticas progressivamente mais eficazes tem tido um impacto positivo na história da doença. Porém, a resistência dos tumores à terapia, nomeadamente a quimiorresistência, surge como obstáculo ao sucesso terapêutico, culminando em menores sobrevida livre de doença e sobrevida global. É, por isso, de grande importância a compreensão dos mecanismos envolvidos neste fenómeno. A via RANKL-RANK está envolvida no desenvolvimento mamário fisiológico e na carcinogénese deste órgão; existindo uma associação positiva entre a expressão de RANK, elevada incidência de focos pré-neoplásicos, desenvolvimento de adenocarcinomas da mama, e pior prognóstico. No nosso laboratório temos investigado o impacto da expressão de RANK no cancro da mama com expressão positiva para recetores hormonais. Uma das características que observámos nos tumores luminais com sobreexpressão de RANK (RANK OE) é a aquisição de um fenótipo estaminal. Geralmente, os tumores são compostos por diferentes populações celulares, incluindo populações com características de estaminalidade, designadas por cancer stem cells (CSC), semelhantes às de células pluripotentes encontradas em tecidos fisiológicos. As CSC apresentam normalmente expressão aumentada de bombas de efluxo, associada a quimioresistência. Assim, o objetivo deste trabalho foi avaliar a sensibilidade à quimioterapia das células RANK OE. As células RANK OE mostraram ser resistentes ao paclitaxel e doxorubicina, exceto quando na presença de osteoprotegerina (OPG), que bloqueia a via RANKL-RANK. O bloqueio de bombas de efluxo com novobiocina foi capaz de sensibilizar as células parentais à quimioterapia, mas não teve efeito adicional nas células RANK OE, que sobreexpressam ABCB1/MDR1. Em tumores luminais da mama humanos observámos uma correlação positiva entre a expressão de RANK e dos transportadores ABCB1 e ABCG2. Assim, a sensibilização à quimioterapia após bloqueio da via RANKL-RANK por OPG demonstra possibilidades de abordagens terapêuticas futuras.
Breast cancer constitutes globally one of the most common forms of cancer, having also high associated mortality. The development of incrementally more effective therapies has had a positive impact on the history of the disease. However, the resistance of tumors to therapy, namely chemoresistance, stands as an obstacle to therapeutic success, culminating in lower disease-free survival and overall survival. It is, therefore, of great importance the understanding of the mechanisms involved in this phenomenon. The RANKL-RANK pathway is involved in the physiological mammary development and in the carcinogenesis of this organ; and there is a positive association between RANK expression, high incidence of pre-neoplastic foci, development of breast adenocarcinomas, and a worse prognosis. In our laboratory we have investigated the impact of RANK expression on hormone receptor-positive breast cancer. One of the characteristics observed in luminal tumors with overexpression of RANK (RANK OE) is the acquisition of a stem phenotype. Generally, tumors are composed of different cell populations, including the termed cancer stem cells (CSC) which manifest stemness proprieties similar to those of pluripotent cells found in physiological tissues. CSCs usually exhibit increased expression of efflux pumps, associated with chemoresistance. Thus, the aim of this study was to evaluate the sensitivity to chemotherapy of RANK OE cells. RANK OE cells were found to be resistant to paclitaxel and doxorubicin, except when in the presence of osteoprotegerin (OPG), which blocks the RANKL-RANK pathway. Blockade of efflux pumps with novobiocin was able to sensitize parental cells to chemotherapy but had no additional effect on RANK OE cells, which overexpress ABCB1/MDR1. In human breast luminal tumors we observed a positive correlation between RANK expression and ABCB1 and ABCG2 transporters. Therefore, sensitization to chemotherapy after blockade of the RANKL-RANK pathway by OPG demonstrates possibilities for future therapeutic approaches.
Breast cancer constitutes globally one of the most common forms of cancer, having also high associated mortality. The development of incrementally more effective therapies has had a positive impact on the history of the disease. However, the resistance of tumors to therapy, namely chemoresistance, stands as an obstacle to therapeutic success, culminating in lower disease-free survival and overall survival. It is, therefore, of great importance the understanding of the mechanisms involved in this phenomenon. The RANKL-RANK pathway is involved in the physiological mammary development and in the carcinogenesis of this organ; and there is a positive association between RANK expression, high incidence of pre-neoplastic foci, development of breast adenocarcinomas, and a worse prognosis. In our laboratory we have investigated the impact of RANK expression on hormone receptor-positive breast cancer. One of the characteristics observed in luminal tumors with overexpression of RANK (RANK OE) is the acquisition of a stem phenotype. Generally, tumors are composed of different cell populations, including the termed cancer stem cells (CSC) which manifest stemness proprieties similar to those of pluripotent cells found in physiological tissues. CSCs usually exhibit increased expression of efflux pumps, associated with chemoresistance. Thus, the aim of this study was to evaluate the sensitivity to chemotherapy of RANK OE cells. RANK OE cells were found to be resistant to paclitaxel and doxorubicin, except when in the presence of osteoprotegerin (OPG), which blocks the RANKL-RANK pathway. Blockade of efflux pumps with novobiocin was able to sensitize parental cells to chemotherapy but had no additional effect on RANK OE cells, which overexpress ABCB1/MDR1. In human breast luminal tumors we observed a positive correlation between RANK expression and ABCB1 and ABCG2 transporters. Therefore, sensitization to chemotherapy after blockade of the RANKL-RANK pathway by OPG demonstrates possibilities for future therapeutic approaches.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2019
Palavras-chave
Cancro da mama Sub-tipo luminal Quimiorresistência Ligante RANK Receptor activador de factor nuclear kappa-B Oncobiologia