With comprehensive analyses using mouse genetic knockout, tissue arrays based on breast cancer patient specimens, and a xenograft breast tumor model, our work demonstrates the synergism between KLF4 and PARP1 in tumorigenesis with respect to cancer therapy for the first time, thus providing a new therapeutic strategy to kill BRCA1‐proficient TNBC tumors by synthetic lethality through suppressing KLF4 in combination with blocking PARP1 function (Fig 9). Here, KLF4 is linked to breast carcinoma.