Highlights d 52% of breast tumors have an alteration in at least one SR protein family member d S... more Highlights d 52% of breast tumors have an alteration in at least one SR protein family member d SRSF4, SRSF6, or TRA2b promotes mammary cell proliferation and invasion d SRSF4, SRSF6, or TRA2b regulates shared spliced isoforms associated with cancer hallmarks d TRA2b is regulated by MYC and plays a role in breast cancer metastasis SUMMARY Misregulation of alternative splicing is a hallmark of human tumors, yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer and uncover differences and redundancies in their targets and biological functions. We identify splicing factors frequently altered in human breast tumors and assay their oncogenic functions using breast organoid models. We demonstrate that not all splicing factors affect mammary tumorigenesis in MCF-10A cells. Specifically, the upregulation of SRSF4, SRSF6, or TRA2b disrupts acinar morphogenesis and promotes cell proliferation and invasion in MCF-10A cells. By characterizing the targets of these oncogenic splicing factors, we identify shared spliced isoforms associated with well-established cancer hallmarks. Finally, we demonstrate that TRA2b is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast cancer patient survival.
Highlights d 52% of breast tumors have an alteration in at least one SR protein family member d S... more Highlights d 52% of breast tumors have an alteration in at least one SR protein family member d SRSF4, SRSF6, or TRA2b promotes mammary cell proliferation and invasion d SRSF4, SRSF6, or TRA2b regulates shared spliced isoforms associated with cancer hallmarks d TRA2b is regulated by MYC and plays a role in breast cancer metastasis SUMMARY Misregulation of alternative splicing is a hallmark of human tumors, yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer and uncover differences and redundancies in their targets and biological functions. We identify splicing factors frequently altered in human breast tumors and assay their oncogenic functions using breast organoid models. We demonstrate that not all splicing factors affect mammary tumorigenesis in MCF-10A cells. Specifically, the upregulation of SRSF4, SRSF6, or TRA2b disrupts acinar morphogenesis and promotes cell proliferation and invasion in MCF-10A cells. By characterizing the targets of these oncogenic splicing factors, we identify shared spliced isoforms associated with well-established cancer hallmarks. Finally, we demonstrate that TRA2b is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast cancer patient survival.
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Papers by Ian Hua