Chen Yi-Yu, Ge Jing-Yu, Zhu Si-Yuan, Shao Zhi-Ming, Yu Ke-Da
Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, 200032, Shanghai, P. R. China.
Human Phenome Institute, Fudan University, 825 Zhangheng Road, 201203, Shanghai, P. R. China.
Nat Commun. 2022 Feb 10;13(1):791. doi: 10.1038/s41467-022-28452-z.
Copy number alterations (CNAs) are pivotal genetic events in triple-negative breast cancer (TNBC). Here, our integrated copy number and transcriptome analysis of 302 TNBC patients reveals that gene alpha-endosulfine (ENSA) exhibits recurrent amplification at the 1q21.3 region and is highly expressed in TNBC. ENSA promotes tumor growth and indicates poor patient survival in TNBC. Mechanistically, we identify ENSA as an essential regulator of cholesterol biosynthesis in TNBC that upregulates the expression of sterol regulatory element-binding transcription factor 2 (SREBP2), a pivotal transcription factor in cholesterol biosynthesis. We confirm that ENSA can increase the level of p-STAT3 (Tyr705) and activated STAT3 binds to the promoter of SREBP2 to promote its transcription. Furthermore, we reveal the efficacy of STAT3 inhibitor Stattic in TNBC with high ENSA expression. In conclusion, the amplification of ENSA at the 1q21.3 region promotes TNBC progression and indicates sensitivity to STAT3 inhibitors.
拷贝数改变（CNAs）是三阴性乳腺癌（TNBC）中的关键遗传事件。在此，我们对302例TNBC患者进行的综合拷贝数和转录组分析显示，基因α-内磺肽（ENSA）在1q21.3区域呈现反复扩增，且在TNBC中高表达。ENSA促进肿瘤生长，并提示TNBC患者预后不良。从机制上来说，我们确定ENSA是TNBC中胆固醇生物合成的关键调节因子，它上调了胆固醇生物合成中的关键转录因子——固醇调节元件结合转录因子2（SREBP2）的表达。我们证实ENSA可增加p-STAT3（Tyr705）的水平，并且活化的STAT3与SREBP2的启动子结合以促进其转录。此外，我们揭示了STAT3抑制剂Stattic对高表达ENSA的TNBC的疗效。总之，1q21.3区域的ENSA扩增促进TNBC进展，并提示对STAT3抑制剂敏感。
