An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer [RNA-seq]

Highly accessible genomic super-enhancers often upregulate tumor-promoting genes in cancer, yet the role of genomic variation within them remains unclear. We identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. Our study revealed that a common germline insertion variant within the super-enhancer is associated with better progression-free survival in breast cancer patients and reduced chromatin accessibility at the super-enhancer locus. By deleting the insertion allele in breast cancer cells, we observed increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, delayed cell death, and reduced infiltration of CD80+ pro-inflammatory macrophages—events that promote tumor growth. The absence of the insertion also activated a protumoral transcriptional program through LINC00636 overexpression. Our findings highlight an insertion/deletion variant that fine-tunes the regulatory function of a bifunctional super-enhancer and suggest a protective role for the insertion in breast cancer.