E3 Ubiquitin Ligase UBR5 Drives the Growth and Metastasis of Triple-Negative Breast Cancer

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 , 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..

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

“…TNBC is characterized by the absence of estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor type 2 (HER2) expression, which means that patients with TNBC cannot be treated with endocrine therapy or therapies targeting HER2 (2)(3)(4). Notably, conventional chemotherapy remains the principal treatment for TNBC, but is associated with a high recurrence rate (5,6).…”

Cluster of differentiation 147 mediates chemoresistance in breast cancer by affecting vacuolar H+-ATPase expression and activity

“…Following overnight incubation, various concentrations of the anticancer drugs epirubicin or docetaxel (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) was added into the medium and cultured for 72 h, and then the cell viability was measured by an SRB assay (34,35). Briefly, the cells were fixed with 10% trichloroacetic acid for 30 min at 4˚C and stained with 0.4% (w/v) SRB (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) in 1% acetic acid solution for 30 min.…”

Control of MYC-dependent apoptotic threshold by a co-amplified ubiquitin E3 ligase UBR5

“…Recently UBR5 has been shown to target substrates also through other recognition mechanisms than N-terminal recognition (Shen, Qiu et al, 2018). UBR5 is essential for mammalian development (Saunders, Hird et al, 2004), and has been linked to both protumourigenic and tumour suppressor activities (Clancy, Henderson et al, 2003, Liao, Song et al, 2017, Saunders et al, 2004. However, the mechanism by which UBR5 would promote tumour growth, and how the protumourigenic effects of UBR5 in human cancer cells (Clancy et al, 2003, can be consolidated with its suggested role as a tumour suppressor in Drosophila (Clancy et al, 2003, Saunders et al, 2004, remains as critical unanswered questions (Shearer et al, 2015).…”