Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis

Yi-Yu Chen,Jing-Yu Ge,Si-Yuan Zhu,Ke-Da Yu,Zhi-Ming Shao

doi:10.1038/s41467-022-28452-z

Abstract

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.

Highlights

Copy number alterations (CNAs) are pivotal genetic events in triple-negative breast cancer (TNBC)
We further investigated the difference in 1q21.3 alteration between different subtypes of breast cancer in the The Cancer Genome Atlas (TCGA) cohort
We explored whether the inhibitory effect of ENSA knockdown on p-STAT3 was dependent on protein phosphatase 2A (PP2A), a known protein phosphatase whose function is inhibited by direct interaction with ENSA

Summary

Introduction

Copy number alterations (CNAs) are pivotal genetic events in triple-negative breast cancer (TNBC). 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. Triple-negative breast cancer (TNBC) accounts for approximately 10–20% of all breast cancer cases It is characterized by negative estrogen receptor (ER) and progestogen receptor (PR) expression and the lack of overexpression of HER2 ( defined by lack of ERBB2 amplification)[1]. Chemotherapy remains the standard of care for TNBC, a subset of patients shows limited responsiveness and develops advanced diseases due to a lack of effective targeted therapy and predictive markers in this heterogeneous disease[5,6]. The transcriptional activation of sterol regulatory element-binding transcription factor 2 (SREBP2) by phosphorylated STAT3 (pSTAT3) played a critical role in ENSA-induced cholesterol metabolism dysregulation. Hindering STAT3 phosphorylation resulted in tumor inhibition in TNBC with high

Methods

Results

Conclusion