一个基因组缺失变异体控制超级增强子驱动的LINC00636和CD47过表达以促进乳腺癌肿瘤细胞存活

Dysregulated gene expression in cancer is often driven by epigenetic reprogramming of non-coding regions such as super-enhancers (SEs). These large enhancer clusters are rarely active in normal tissues but can drive overexpression of genes that promote malignant traits, including immune evasion. Previously we have shown that SEs are linked to chemotherapy resistance and anti-apoptotic gene expression in triple-negative breast cancer (TNBC). Although SEs are promising therapeutic targets, their large size makes them difficult to target effectively in cancer therapy. This limitation underscores the need to identify smaller, functionally critical regions within SEs that can serve as precise therapeutic entry points.The goal of this research is to define and functionally validate core elements within breast cancer-specific SEs that are necessary and sufficient to drive immune escape. We hypothesize that these core elements, alone or in combination, act as molecular drivers of malignancy by aberrantly activating the immune-suppressive gene CD47 and the regulatory long non-coding RNA LINC00636 .Our rationale stems from the discovery of a breast cancer-specific SE harboring a germline insertion/deletion (InDel) variant that regulates CD47 and LINC00636 expression. CRISPR deletion of this variant in engineered breast cancer cells increased chromatin accessibility of the SE region, leading to upregulation of CD47 and LINC00636 , enhanced resistance to nutrient-deprivation-induced apoptosis (via CD47 ), activation of senescence (driven by elevated LINC00636 ), and delayed cell death. RNA-seq analyses of cells lacking the insertion and cells with high LINC00636 expression revealed a shared immunosuppressive and pro-survival transcriptional program, including increased CXCL17, STAT1, CXCL8 , and ANGPTL4 -genes associated with tumor immune signaling, senescence and apoptosis resistance. In macrophage-competent xenograft models, deletion of the variant reduced anti-tumor macrophage infiltration, supporting activation of an immune-evasive state. Clinically, breast cancer patients carrying the insertion allele show improved progression-free survival when compared to patients homozygous for the deletion-demonstrating the clinical relevance of discrete SE elements.Together, our findings identify a common InDel variant as a minimal core element that fine-tunes the regulatory activity of a bifunctional SE controlling CD47 and LINC00636 . Our work provides new insight into SE-mediated gene dysregulation in breast cancer and highlights the therapeutic potential of targeting discrete SE components rather than entire enhancer clusters.