SETD4 marks Quiescent Cancer Stem Cells with Chemoradiotherapy Resistance in Breast Cancer of MMTV-PyMT Mouse

We isolated quiescent CSCs using chemoradiotherapy resistance assays on tumors of MMTV-PyMT transgenic (specific breast cancer model) mice. We found that quiescent CSCs specifically expressed SETD4 without exception, and beyond activation exhibited high capacity of tumor-initiation in vivo and tumorsphere formation in vitro. Quiescent CSCs expressed high levels of ALDH1 and CD44 and low levels of CD24, that corresponds with their use as breast CSCs markers. Quiescent CSCs were showed to be resistant and able to survive under chemoradiotherapy treatment in either in vivo or in vitro models. Similarly, SETD4 overexpression caused cells extracted from tumors to exhibit clear chemoradiotherapy resistance. Transcriptomic analysis revealed that the molecular processes associated with cellular quiescence included those of DNA damage response and the Wnt/β-catenin signaling pathway. Together with our previous results, these findings showed that SETD4 marks quiescent CSCs and suggest that SETD4-marked quiescent CSCs could be used as key targets in clinical treatment for multiple cancers. RNA sequencing was performed in quiescent CSCs and activated CSCs. Transcriptome profiles of three replicates in each group were compared.