Transcriptional Repressor GATA Binding 1–mediated Repression Of SRY-box 2 Expression Suppresses Breast Cancer Stem Cell Functions And Tumor Initiation

Breast cancer is a major cancer type in woman.GATA factors play important roles both in development and cancer.Typical GATA factors(GATA1-6)are implicated in inducing differentiation of embryonic stem cells and modulating CSC functions.Transcriptional repressor GATA binding 1(TRPS1),an atypical member of GATA transcriptional factor family,implicates in stem cell functions as its overexpression promotes differentiation of chondrogenic cells.However,whether and how TRPS1 contributes to CSC functions and tumor initiation is mostly unknown.Cancer stem cells(CSCs)have been reported in a variety of cancers.SRY-box 2(SOX2)is a member of the SOX family of transcription factors and has been shown to play a critical role in maintaining the functions of CSCs and promoting tumor initiation.However,the underlying mechanisms for the transcriptional regulation of the SOX2 gene in CSCs are unclear.In this study,using in silico and experimental approaches,we identified TRPS1 as a critical transcriptional regulator that represses SOX2 expression and thereby suppresses cancer stemness and tumorigenesis.Mechanistically,TRPS1 repressed SOX2 expression by directly targeting the consensus GATA-binding element in the SOX2 promoter as elucidated by ChIP and luciferase reporter assays.Of note,in vitro mammosphere formation assays in culture and in vivo xenograft tumor initiation experiments in mouse models revealed that TRPS1-mediated repression of SOX2 expression suppresses CSC functions and tumor initiation.Taken together,our study provides detailed mechanistic insights into CSC functions and tumor initiation by the TRPS1–SOX2 axis.