Role of Thyroid Hormones in breast cancer resistance to chemotherapy

Johanna Abigail Díaz Albuja¹, Cinthia Rosemblit¹, Mercedes Dibernardi¹, Florencia Cayrol¹, Helena Sterle¹, Alejandrea Paulazo¹, Graciela Cremaschi1°, María Celeste Díaz Flaqué¹

Breast cancer (BC) is the leading cause of cancer death in women. Combination chemotherapy is one of the important adjuvant therapies for BC after surgery. The efficacy of drug treatment is often limited by tumor cell resistance. Many BC acquire multidrug resistance (MDR) by upregulating the level or activity of membrane proteins such as Pgp, which enable the exclusion of cytotoxic substances from the intracellular environment. Previously we demonstrated that Thyroid Hormones (TH) modulate chemotherapy response in T cell lymphoma (TCL). However little is known about the modulation of TH in the mechanisms that lead to chemotherapy resistance in BC cells. Bexarotene (Bex) is an oral retinoid-X-receptor agonist that is effective for the treatment in cutaneous TCL and there are ongoing clinical trials studying its role for BC treatment in combination with chemotherapeutic drugs. However thyroid dysfunction is recognized as an important side effect of Bex treatment, potentially manageable by TH administration. We found that Bex treatment reduces intracellular drug accumulation in MDA MB 231 cells, while TH revert this effect. Bioinformatics studies revealed alterations of genes significantly associated with drug response and genes involved in the TH signaling pathways in paclitaxel resistant-BC cells vs paclitaxel resistant-BC cells treated with Bex. These results point out the role of TH in BC resistance to chemotherapy and strengthen the importance to check thyroid status during BC therapy.