Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis
| Autor: | Adrian R. Krainer, Shipra Das, Martin Fan, Nathan K. Leclair, Leo Hu, Olga Anczuków, Laura Urbanski, Adam Geier, SungHee Park, Martin Akerman, Ian Hua, Senthil K. Muthuswamy, Joshy George, Kuan-Ting Lin, Mattia Brugiolo, Anil K. Kesarwani |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
RNA Splicing Breast Neoplasms Biology General Biochemistry Genetics and Molecular Biology Article Metastasis 03 medical and health sciences Splicing factor 0302 clinical medicine Breast cancer SR protein medicine Humans Neoplasm Metastasis skin and connective tissue diseases lcsh:QH301-705.5 Triple-negative breast cancer Alternative splicing Cancer medicine.disease 030104 developmental biology lcsh:Biology (General) RNA splicing Cancer research RNA Splicing Factors 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 29, Iss 9, Pp 2672-2688.e7 (2019) |
| ISSN: | 2211-1247 |
| Popis: | 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 TRA2β 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 TRA2β is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast cancer patient survival. : Park et al. demonstrate that >50% of human breast tumors exhibit an alteration in one of the splicing factors from the SR protein family. Using in vitro and in vivo breast cancer models, they identify three splicing factors that promote cell proliferation and invasion by regulating isoforms associated with cancer hallmarks. Keywords: alternative RNA splicing, breast cancer, splicing factor, SR protein, metastasis, MYC, TRA2-beta, triple negative breast cancer |
| Databáze: | OpenAIRE |
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