1. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China.
2. Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China.
3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
4. SARI Center for Stem Cell and Nanomedicine, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, People's Republic of China.
5. Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
6. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, People's Republic of China.
7. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs.
Methods: Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylation (C/P) genes was used to identify key C/P factors.
Results: We established an unconventional APA subtyping system composed of four stable subtypes: 1) luminal androgen receptor (LAR), 2) mesenchymal-like immune-activated (MLIA), 3) basal-like (BL), 4) suppressed (S) subtypes. Patients in the S subtype had the worst disease-free survival comparing to other patients (log-rank p = 0.021). Enriched clinically actionable pathways and putative therapeutic APA events were analyzed among each APA subtype. Furthermore, CPSF1 and PABPN1 were identified as the master C/P factors in regulating APA events and TNBC proliferation. The depletion of CPSF1 or PABPN1 weakened cell proliferation, enhanced apoptosis, resulted in cell cycle redistribution and a reversion of APA events of genes associated with tumorigenesis, proliferation, metastasis and chemosensitivity in breast cancer.
Conclusions: Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC.
Keywords: alternative polyadenylation, subtype, triple-negative breast cancer, CPSF1, PABPN1