TGFbeta type I receptor signaling mediates histamine-ionizing radiation crosstalk in epithelial mesenchymal transition progress and cancer stem-like cells enrichment in breast cancer cells

TAMARA GALARZA; NORA MOHAMAD; GRACIELA CRICCO; GABRIELA MARTIN

Congreso; Reunión anual de Sociedades de Biociencias. SAIC. SAI. SAFIS; 2022

Tumor radio-resistance favours recurrence and progression of the disease in patients due to cells that survive radiotherapy. As well, epithelial mesenchymal transition (EMT) is relevant for the acquisition and maintenance of cancer stem-like cells (CSC-like) properties in tumor cells. Likewise, activation of the TGFbeta-1/TGFbeta type I receptor (TBRI) pathway promotes radio-resistance by inducing EMT progression and CSC-like enrichment. We have previously demonstrated in breast tumor cells the dual role of histamine (Ha) on the radio-induced EMT process: favouring EMT at ≤ 1 μM and hindering it at ≥10 μM. In this study, we aimed to evaluate a link between Ha action on radio-induced EMT and the activation of TβRI signalling, in MCF-7 and MDA-MB-231 breast cancer cells. Cells were treated with 1 μM Ha (low Ha) or 20 μM (high Ha) and with the selective inhibitor of TGFBRI A83-01; 24 h later cells were 2Gy irradiated. After 5 days, indirect immunofluorescence assays were performed to evaluate positive nuclei for P-Smad2/3 (canonical TBRI effector), Slug and β-catenin proteins (EMT molecular markers). In addition, mammosphere formation (stem cells surrogate assay), cell migration using transwell chambers, morphology (EMT functional traits) and clonogenic capacity were evaluated. In both cell lines, A83-01 prevented the alteration in cell morphology and the increase in mammospheres, colonies and migrated cells number due to irradiation (p