Increased autophagy blocks HER2-mediated breast tumorigenesis

Silvia Vega-Rubín-De-Celis, Zhongju Zou, Álvaro F. Fernández, Bo Ci, Min Kim, Guanghua Xiao, Yang Xie, Beth Levine

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Allelic loss of the autophagy gene, beclin 1/BECN1, increases the risk of patients developing aggressive, including human epidermal growth factor receptor 2 (HER2)-positive, breast cancers; however, it is not known whether autophagy induction may be beneficial in preventing HER2-positive breast tumor growth. We explored the regulation of autophagy in breast cancer cells by HER2 in vitro and the effects of genetic and pharmacological strategies to increase autophagy on HER2-driven breast cancer growth in vivo. Our findings demonstrate that HER2 interacts with Beclin 1 in breast cancer cells and inhibits autophagy. Mice with increased basal autophagy due to a genetically engineered mutation in Becn1 are protected from HER2-driven mammary tumorigenesis, and HER2 fails to inhibit autophagy in primary cells derived from these mice. Moreover, treatment of mice with HER2-positive human breast cancer xenografts with the Tat-Beclin 1 autophagy-inducing peptide inhibits tumor growth as effectively as a clinically used HER2 tyrosine kinase inhibitor (TKI). This inhibition of tumor growth is associated with a robust induction of autophagy, a disruption of HER2/Beclin 1 binding, and a transcriptional signature in the tumors distinct from that observed with HER2 TKI treatment. Taken together, these findings indicate that the HER2-mediated inhibition of Beclin 1 and autophagy likely contributes to HER2-mediated tumorigenesis and that strategies to block HER2/Beclin 1 binding and/or increase autophagy may represent a new therapeutic approach for HER2-positive breast cancers.

Original languageEnglish (US)
Pages (from-to)4176-4181
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number16
DOIs
StatePublished - Apr 17 2018

Keywords

  • Autophagy
  • Beclin 1
  • HER2
  • breast cancer

ASJC Scopus subject areas

  • General

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