THYROID HORMONES EFFECTS IN BEXAROTENE TREATMENT OF BREAST CANCER CELLS

DIAZ ALBUJA JA; ROSEMBLIT C; DEBERNARDI MM; CAYROL MF; STERLE HA; PAULAZO MA; CREMASCHI GA; DIAZ FLAQUÉ MC

Congreso; Reunion Conjunta de Sociedades de Biociencias 2019; 2019

Chemoresistance is a major cause of cancer treatment failure. Many breast cancer (BC) cells develop chemoresistance by diminishing intracellular drug accumulation, upregulating protein levels or activating transporters like MDR1. Previously we demonstrated that thyroid hormones (THs) modulate chemotherapy response in T cell lymphoma (TCL) cells. However, in BC cells little is known about these mechanisms that lead to tumor chemotherapy resistance and are crucial to assure the success of treatment. Bexarotene (Bex) is an oral retinoid-X- receptor agonist that is effective for the treatment of early and advanced-stage in cutaneous TCL and there are ongoing clinical trials to determine its role in both BC treatment and prevention.However thyroid dysfunction is recognized as an important side effect of such therapies, potentially manageable by THs administration. To study how THs affect MDA-MB-231 drug transport, rhodamine 123 (RHO123) incorporation assay was performed. Our results shown that MDA-MB-231 cells incorporate RHO123 in a time dependent manner, reaching to a plateau at 3 h, and this effect was not affected by THs treatment. On the other hand, we found that THs increase RHO123 exclusion at 1 h in BC cells (p<0.01). We evaluate if Bex can induce MDR associated protein clearance from MDA-MB-231 cells by secreting extracellular lipid vesicles (EVs). We found that Bex treatment reduces intracellular RHO123 accumulation and THs reverts this effect. Also, by electron microscopy we found that Bex induces EVs release and THs increases this effect. Our data suggest that the requirement of THs replacement therapy may affect Bex treatment in BC.