In sum, we identified down-regulation of TSHZ2 as a key for the release of GLI1 from a CtBP-containing corepressor complex to lead the activated expression of GLI1 target genes during mammary tumorigenesis, and we speculate that in addition to GLI1 TSHZ2 might control other transcriptional regulators, which highlight the role of TSHZ2 in the development and progression of breast cancer. Here, CTBP1 is linked to breast cancer.