Superenhancer drives a tumor-specific splicing variant of MARCO to promote triple-negative breast cancer progression

• DOI: 10.1073/pnas.2207201119
• Publication Date: 2022-11-07T20:17:01Z
• Authors: Yun-Song Yang; Xi Jin; Qin Li; Yi-Yu Chen; Fenfang Chen; Hena Zhang; Ying Su; Yi Xiao; Gen-Hong Di; Yi-Zhou Jiang; Shenglin Huang; Zhi-Ming Shao
• Keywords: Triple-negative breast cancer

The transcription variation, leading to various forms of transcripts and protein diversity, remains largely unexplored in triple-negative breast cancers (TNBCs). Here, we presented a comprehensive analysis RNA splicing cancer illustrate the biological function clinical implications tumor-specific (TSTs) arising from these junctions. Aberrant or TSTs were frequently harbored TNBC correlated with poor outcome. We discovered variant macrophage receptor collagenous structure–TST (MARCO-TST), which was distinguished myeloid cell-specific wild-type MARCO. MARCO-TST expression associated outcomes patients could promote tumor progression vitro vivo. Mechanically, interacted PLOD2 enhanced stability HIF-1α, resulted metabolic dysregulation form hypoxic microenvironment. initiated de novo alternative initiation site that activated by superenhancer. Tumors conferred greater sensitivity bromodomain extraterminal inhibitors. This treatment strategy further validated patient-derived organoids. In conclusion, our results revealed variation landscape TNBC, highlighting as crucial oncogenic transcript therapeutic target.