Triple negative breast cancer (TNBC) is one of the breast cancer subtypes with high degree of malignancy. Compared with other breast cancer subtypes, it has the characteristics of high metastasis rate, high proportion of cell proliferation, and poor prognosis. There is so far no specific targeted drugs to treat TNBC.  

Through bioinformatics analysis, the research group led by Prof. JIAO Baowei at Kunming Institute of Zoology of Chinese Academy of sciences revealed that TNBC displays a unique Alternative Splicing (AS) pattern in comparison with other breast cancer subtypes. This special splicing pattern and its regulatory factors may serve as potential targets for the treatment of TNBC. The study was published in PNAS.

TDP43, one of the splicing factors, which is highly expressed in TNBC, was found to act as a major splicing regulator of TNBC’s unique AS profile. Knockdown of TDP43 in TNBC cell lines inhibited cell proliferation, cell metastasis and invasion. Whereas, overexpressed TDP43 in immortalized breast epithelial cells promoted cell proliferation and malignancy.  

Subsequent high throughput sequencing and functional assays demonstrated that TDP43 regulates AS in coordination with SRSF3, another splicing factor. The TDP43/SRSF3 complex controls specific splicing events, including downstream genes PAR3 and NUMB.

Moreover, the researchers found that 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. Therefore, the TDP43/SRSF3 complex and downstream PAR3 isoform are potential therapeutic targets for TNBC.  

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, National Key Research and Development Program of China, National Science Foundation of China, and Open Project from the State Key Laboratory of Genetic Resources and Evolution. 

Working model of TDP43 in TNBC progression (Image by JIAO’s group)