In this study, we revealed a novel SIRT1-PRRX1-KLF4 circuitry, whereby SIRT1 deacetylates and thus prevents the proteasomal degradation of PRRX1.We demonstrate that PRRX1 exerts its stemness-promoting effect on breast cancer cells by orchestrating the crosstalk between epithelial and proliferative states via transcriptional regulation of KLF4. Loss of PRRX1 disinhibits KLF4 transcription, which activates functional breast CSC marker ALDH1A1 and ALDH1A3. The gene discussed is KLF4; the disease is breast cancer.