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We have earlier characterized increased TGF-β signaling in radioresistant breast cancer cells. In this study, we wanted to determine the effect of prolonged treatment of TGF-βR inhibitor SB431542 on radiation-induced signaling, viz., genes regulating apoptosis, EMT, anti and pro-inflammatory cytokines. Breast cancer cells were pretreated with TGF-βR inhibitor (SB 431542) followed by exposure to 6 Gy and recovery period of 7 days (D7-6G). We assessed cell survival by MTT assay, cytokines by ELISA and expression analysis by RT-PCR, flow cytometry, and western blot. We carried out migration assays using trans well inserts. We performed bioinformatics analyses of human cancer database through cBioportal. There was an upregulation of TGF-β1 and 3 and downregulation of TGF-β2, TGF-βR1, and TGF-βR2 in invasive breast carcinoma samples compared to normal tissue. TGF-β1 and TNF-α was higher in radioresistant D7-6G cells with upregulation of pSMAD3, pNF-kB, and ERK signaling. Pretreatment of D7-6G cells with TGF-βR inhibitor SB431542 abrogated pSMAD3, increased proliferation, and migration along with an increase in apoptosis and pro-apoptotic genes. This was associated with hybrid E/M phenotype and downregulation of TGF-β downstream genes, HMGA2 and Snail. There was complete agreement in the expression of mRNA and protein data in genes like vimentin, Snail and HMGA2 in different treatment groups. However, there was disagreement in expression of mRNA and protein in genes like Bax, Bcl-2, E-cadherin, Zeb-1 among the different treatment groups indicating post-transcriptional and post-translational processing of these proteins. Treatment of cells with only SB431542 also increased expression of some E/M genes indicating TGF-β independent effects. Increased IL-6 and IL-10 secretion by SB431542 along with increase in pSTAT3 and pCREB1 could probably explain these TGF-β/Smad3 independent effects. These results highlight that TGF-β-pSMAD3 and TNF-α-pNF-kB are the predominant signaling pathways in radioresistant cells and possibility of some TGF-β/Smad3 independent effects on prolonged treatment with the drug SB431542.

Effects of prolonged treatment of TGF-βR inhibitor SB431542 on radiation-induced signaling in breast cancer cells