Abnormal gene expression plays key role in cancer development. A core promoter is located around the transcriptional start site. Through interaction between core promoter sequences and transcriptional factors, core promoter controls transcriptional initiation. We hypothesized that in cancer, core promoter sequences could be mutated to interfere the interaction with transcriptional factors, resulting in altered transcriptional initiation and abnormal gene expression and cancer development. We used triple-negative breast cancer (TNBC) as a model to test our hypothesis. We collected genome-wide core promoter variants from 279 TNBC genomes. After extensive filtering of normal genomic polymorphism, we identified 19,427 recurrent somatic variants in 1238 core promoters of 1274 genes and 1694 recurrent germline variants in 272 core promoters of 294 genes. Many of the affected genes were oncogenes and tumor suppressors. Analysis of RNA-seq data from the same patient cohort identified increased or decreased gene expression in 439 somatic and 85 germline variants-affected genes, and the results were validated by luciferase reporter assay. By comparing with the core promoter variation data from 610 unclassified breast cancer, we observed that core promoter variants in TNBC were highly TNBC-specific. We further identified the drugs targeting the genes with core promoter variation. Our study demonstrates that core promoter is highly mutable in cancer, and can play etiological roles in TNBC and other types of cancer through influencing transcriptional initiation.