E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple-negative breast cancer

Liqiu Liao, Mei Song, Xin Li, Lili Tang, Tuo Zhang, Lixing Zhang, Yihang Pan, Lotfi Chouchane, Xiaojing Ma

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Patients with triple-negative breast cancers (TNBC) are at high risk for recurrence and metastasis at an early time despite standard treatment, underscoring the need for novel therapeutic modalities. Here, we report for the first time a distinctive and profound role of the E3 ubiquitin ligase UBR5 in the growth and metastasis of TNBC. An analysis of primary TNBC specimen by whole-exon sequencing revealed strong gene amplifications of UBR5 associated with the disease. UBR5 overexpression in TNBC tissues was confirmed at mRNA and protein levels. CRISPR/Cas9-mediated deletion of ubr5 in an experimental murine mammary carcinoma model of TNBC dramatically abrogated tumor growth and metastasis in vivo, which could be reversed completely via reconstitution with wild-type UBR5 but not a catalytically inactive mutant. Loss of UBR5 caused an impairment in angiogenesis within the tumor, associated with increased apoptosis, necrosis, and growth arrest. Absence of UBR5 in the tumor triggered aberrant epithelial-to-mesenchymal transition, principally via abrogated expression of E-cadherin, which resulted in severely reduced tumor metastasis to secondary organs. Use of NOD/SCID mice revealed that tumor-derived UBR5 facilitated tumor growth in a manner completely dependent upon immune cells in the microenvironment, whereas it promoted metastasis in a tumor cell-autonomous fashion. Our findings unveil UBR5 as a novel and critical regulator of tumor growth, metastasis, and immune response and highlight the potential for UBR5 as an effective therapeutic target for the treatment of highly aggressive breast and ovarian cancers that fail conventional therapy.

Original languageEnglish
Pages (from-to)2090-2101
Number of pages12
JournalCancer Research
Volume77
Issue number8
DOIs
Publication statusPublished - 15 Apr 2017

Fingerprint

Triple Negative Breast Neoplasms
Ubiquitin-Protein Ligases
Neoplasm Metastasis
Growth
Neoplasms
Clustered Regularly Interspaced Short Palindromic Repeats
Breast Neoplasms
Cellular Microenvironment
Therapeutics
Inbred NOD Mouse
Epithelial-Mesenchymal Transition
SCID Mice
Gene Amplification
Cadherins
Ovarian Neoplasms
Exons
Necrosis
Apoptosis
Recurrence
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Liao, L., Song, M., Li, X., Tang, L., Zhang, T., Zhang, L., ... Ma, X. (2017). E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple-negative breast cancer. Cancer Research, 77(8), 2090-2101. https://doi.org/10.1158/0008-5472.CAN-16-2409

E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple-negative breast cancer. / Liao, Liqiu; Song, Mei; Li, Xin; Tang, Lili; Zhang, Tuo; Zhang, Lixing; Pan, Yihang; Chouchane, Lotfi; Ma, Xiaojing.

In: Cancer Research, Vol. 77, No. 8, 15.04.2017, p. 2090-2101.

Research output: Contribution to journalArticle

Liao, L, Song, M, Li, X, Tang, L, Zhang, T, Zhang, L, Pan, Y, Chouchane, L & Ma, X 2017, 'E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple-negative breast cancer', Cancer Research, vol. 77, no. 8, pp. 2090-2101. https://doi.org/10.1158/0008-5472.CAN-16-2409
Liao, Liqiu ; Song, Mei ; Li, Xin ; Tang, Lili ; Zhang, Tuo ; Zhang, Lixing ; Pan, Yihang ; Chouchane, Lotfi ; Ma, Xiaojing. / E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple-negative breast cancer. In: Cancer Research. 2017 ; Vol. 77, No. 8. pp. 2090-2101.
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