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. Cancer Res; 77(8); 2090-101. ©2017 AACR.
Highlights
Triple-negative breast cancer (TNBC), as defined by the negative expression of the estrogen receptor (ER) and progesterone receptor (PR) as well as human epidermal growth factor receptor-2 (HER-2), represents approximately 12% to 17% of all invasive breast carcinomas [1]
We showed that deletion of ubr5 in 4T1 mammary tumor suppressed metastatic lung colonization through mechanisms that go beyond cell-intrinsic regulation of epithelial traits
In the process of tumor metastasis, primary tumor cells would acquire fibroblast-like properties and exhibit reduced cell–cell adhesion and increased motility via epithelial-to-mesenchymal transition (EMT), which represents a fundamentally important process conducive to tumor dissemination [32,33,34]
Summary
Triple-negative breast cancer (TNBC), as defined by the negative expression of the estrogen receptor (ER) and progesterone receptor (PR) as well as human epidermal growth factor receptor-2 (HER-2), represents approximately 12% to 17% of all invasive breast carcinomas [1]. TNBCs are highly aggressive with large tumor mass, high nuclear grade, increased lymph node involvement at the time of diagnosis, contributing to the highest risk of recurrence and metastasis of all breast cancer types at an early time [2]. Because of the heterogeneity and no well-defined molecular targets, patients with metastatic TNBC have a poor survival for 5 years despite standard treatment [3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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