An InDel genomic variant within a bifunctional super-enhancer for LINC00636 and CD47 regulation in breast cancer

Abstract Highly accessible genomic super-enhancers often drive tumor-promoting programs, yet the impact of genomic variation within these regulatory elements remains unclear. Here, we identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. We discovered that a common germline insertion variant within the super-enhancer is associated with reduced chromatin accessibility at the super-enhancer locus. Deletion of the insertion in breast cancer cells increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, enhanced resistance to nutrient-deprivation–induced apoptosis (mediated by CD47), activation of senescence (driven by elevated LINC00636), delayed cell death, and reduced infiltration of CD80⁺ pro-inflammatory macrophages, changes that represent tumor-promoting features. Together, our findings uncover a common insertion-deletion variant that fine-tunes the regulatory activity of a bifunctional super-enhancer, suggest a protective role for the insertion allele, and establish a previously unrecognized role for LINC00636 in senescence and breast cancer biology.