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

Nat Commun. 2022 Feb 10;13(1):791. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cholesterol / biosynthesis*
  • DNA Copy Number Variations*
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • STAT3 Transcription Factor / metabolism
  • Sterol Regulatory Element Binding Protein 2
  • Transcriptome
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / metabolism*
  • Up-Regulation

Substances

  • Intercellular Signaling Peptides and Proteins
  • SREBF2 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Sterol Regulatory Element Binding Protein 2
  • endosulfine
  • Cholesterol