E3 Ubiquitin Ligase UBR5 Drives the Growth and Metastasis of Triple-Negative Breast Cancer.
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 metastasisin 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.Cancer Res; 77(8); 2090-101. ©2017 AACR.
Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Liqiu
L
Liao
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York.
Mei
M
Song
Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Xin
X
Li
Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Lili
L
Tang
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York.
Tuo
T
Zhang
State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Lixing
L
Zhang
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
Yihang
Y
Pan
Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar.
Lotfi
L
Chouchane
Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, Hunan, China. xim2002@med.cornell.edu.|Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York.|State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Xiaojing
X
Ma
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; C117617:UBR5 protein, human; C489244:UBR5 protein, mouse; D044767:Ubiquitin-Protein Ligases