ANALYSIS OF THYROID HORMONE EFFECTS ON THE RELEASE OF EXTRACELLULAR VESICLES AND THEIR ROLE IN CHEMOTHERAPY RESPONSE IN BREAST CANCER

DIAZ ALBUJA, JOHANNA; FAGUNDES, PABLO; TOSAR, JUAN PABLO; CAMPOS HAEDO, M.N.; DEBERNARDI, MERCEDES; GONZALES, GONZALO; MENAY, FLORENCIA; CREMASCHI, GRACIELA A.; DÍAZ FLAQUÉ, M. CELESTE

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

Chemoresistance is a major cause of cancer treatment failure. Extracellular vesicles (EVs) from resistant cells have been associatedwith the transfer of drug resistance to sensitive cells. Many breastcancer cells acquire multidrug resistance (MDR) by upregulatingthe level or activity of membrane proteins such as MDR1, whichenables the exclusion of cytotoxic substances from the intracellularenvironment. Previously we have demonstrated that thyroid hormones (THs) modulate Doxorubicin response in T lymphoma cells.However, related to the chemoresistance of breast cancer cells, littleis known about TH- induced mechanisms that influence tumor chemotherapy response. To this aim we first generate and characterized MDA-MB-231 Doxorubicin-resistant cells (MDA-DR). In thesecells, we found that THs induce the expression of proteins involvedin drug response such as MDR1, BCRP, and CYP3A4 (p < 0,05). Inaddition, we found that THs induce the release of EVs of 80-400 nmin size, as could be seen by nanoparticle analysis and transmissionelectron microscopy. In these EVs, we found protein expression ofMDR1 and BCRP, the major proteins involved in the efflux of cytotoxic agents in breast cancer. Also, CD44 protein, associated withMDR1 transfer from vesicles to cells, was also found by westernblot. Interestingly, the transfer of these EVs to doxorubicin-sensitive MDA-MB- 231 cells modulates the tolerance of sensitive cells tothis drug. In conclusion, THs regulate the release of EVs and theirprotein cargo, containing MDR-transporters that could transfer drugtolerance to sensitive breast cancer cells.