Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin

Tobias Wijshake, Zhongju Zou, Beibei Chen, Lin Zhong, Guanghua Xiao, Yang Xie, John G. Doench, Lynda Bennett, Beth Levine

Research output: Contribution to journalArticlepeer-review

Abstract

Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1–specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin–mediated tumor suppression in breast cancer cells.

Original languageEnglish (US)
Article numbere2020478118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number5
DOIs
StatePublished - Feb 2 2021

Keywords

  • Beclin 1
  • Breast cancer
  • E-cadherin

ASJC Scopus subject areas

  • General

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