Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers
Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers
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剖析三阴性乳腺癌中替代多聚腺苷酸化谱的异质性
DOI：
10.7150/thno.40944
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
--
作者：
Wang, Lei;Lang, Guan-Tian;Shao, Zhi-Ming
背景：三阴性乳腺癌（TNBC）是一种具有高度异质性的侵袭性恶性肿瘤。然而，TNBC的其他聚腺苷化（APA）谱仍然未知。在这里，我们旨在确定tnbc中转录后水平的APA事件的特征。方法：利用转录组芯片数据分析165例TNBC样本和33对正常组织的APA谱。利用针对23个核心裂解和聚腺苷化（C/P）基因的短发夹RNA筛选技术，鉴定关键的C/P因子。结果：我们建立了一个由4个稳定亚型组成的非常规APA亚型系统：1)腔内雄激素受体（LAR）， 2)间充质样免疫激活（MLIA）， 3)基底样（BL）， 4)抑制(S)亚型。与其他患者相比，S亚型患者的无病生存期最差（log-rank p = 0.021）。分析了各APA亚型中丰富的临床可操作通路和推定的治疗性APA事件。此外，CPSF1和PABPN1被鉴定为调节APA事件和TNBC增殖的主C/P因子。CPSF1或PABPN1的缺失削弱了乳腺癌细胞增殖，增强了细胞凋亡，导致细胞周期重新分布，逆转了与肿瘤发生、增殖、转移和化疗敏感性相关基因的APA事件。结论：我们的研究结果促进了对APA中肿瘤异质性调控的理解，并为TNBC的治疗靶点识别提供了新的见解。
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.