Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 15, Pages E3426-E3435Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1714573115
Keywords
breast cancer; alternative splicing; TDP43; SRSF3; PAR3
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Funding
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB13030400]
- National Key Research and Development Program of China [2016YFA0100900]
- National Science Foundation of China [31371502]
- Yunnan Applied Basic Research Project [2016FB038]
- Open Project from the State Key Laboratory of Genetic Resources and Evolution Grant [GREKF14-05]
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Aberrant alternative splicing has been highlighted as a potential hallmark of cancer. Here, we identify TDP43 (TAR DNA-binding protein 43) as an important splicing regulator responsible for the unique splicing profile in triple-negative breast cancer (TNBC). Clinical data demonstrate that TDP43 is highly expressed in TNBC with poor prognosis. Knockdown of TDP43 inhibits tumor progression, including proliferation and metastasis, and overexpression of TDP43 promotes proliferation and malignancy of mammary epithelial cells. Deep sequencing analysis and functional experiments indicate that TDP43 alters most splicing events with splicing factor SRSF3 (serine/arginine-rich splicing factor 3), in the regulation of TNBC progression. The TDP43/SRSF3 complex controls specific splicing events, including downstream genes PAR3 and NUMB. The effect of reduced metastasis and proliferation upon the knockdown of TDP43 or SRSF3 is mediated by the splicing regulation of PAR3 and NUMB exon 12, respectively. The TDP43/SRSF3 complex and downstream PAR3 isoform are potential therapeutic targets for TNBC.
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