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Overexpression of ?-Arrestins inhibits proliferation and motility in triple negative breast cancer cells.

ABSTRACT: ?-Arrestins (?Arrs) are intracellular signal regulating proteins. Their expression level varies in some cancers and they have a significant impact on cancer cell function. In general, the significance of ?Arrs in cancer research comes from studies examining GPCR signalling. Given the diversity of different GPCR signals in cancer cell regulation, contradictory results are inevitable regarding the role of ?Arrs. Our approach examines the direct influence of ?Arrs on cellular function and gene expression profiles by changing their expression levels in breast cancer cells, MDA-MB-231 and MDA-MB-468. Reducing expression of ?Arr1 or ?Arr2 tended to increase cell proliferation and invasion whereas increasing their expression levels inhibited them. The overexpression of ?Arrs caused cell cycle S-phase arrest and differential expression of cell cycle genes, CDC45, BUB1, CCNB1, CCNB2, CDKN2C and reduced HER3, IGF-1R, and Snail. Regarding to the clinical relevance of our results, low expression levels of ?Arr1 were inversely correlated with CDC45, BUB1, CCNB1, and CCNB2 genes compared to normal tissue samples while positively correlated with poorer prognosis in breast tumours. These results indicate that ?Arr1 and ?Arr2 are significantly involved in cell cycle and anticancer signalling pathways through their influence on cell cycle genes and HER3, IGF-1R, and Snail in TNBC cells.

SUBMITTER: Bostanabad SY

PROVIDER: S-EPMC7810837 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Overexpression of β-Arrestins inhibits proliferation and motility in triple negative breast cancer cells.

Bostanabad Saber Yari SY Noyan Senem S Dedeoglu Bala Gur BG Gurdal Hakan H

Scientific reports 20210115 1

β-Arrestins (βArrs) are intracellular signal regulating proteins. Their expression level varies in some cancers and they have a significant impact on cancer cell function. In general, the significance of βArrs in cancer research comes from studies examining GPCR signalling. Given the diversity of different GPCR signals in cancer cell regulation, contradictory results are inevitable regarding the role of βArrs. Our approach examines the direct influence of βArrs on cellular function and gene expr ...[more]

PMID: 33452359

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Project description:Triple-negative breast cancer (TNBC) is an aggressive clinical subtype of breast cancer that is characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor 2 (HER2) overexpression. The TNBC subtype constitutes approximately 10%-20% of all breast cancers, but has no effective molecular targeted therapies. Previous meta-analysis of gene expression profiles of 587 TNBC cases from 21 studies demonstrated high expression of Wnt signaling pathway-associated genes in basal-like 2 and mesenchymal subtypes of TNBC. In this study, we investigated the potential of Wnt pathway inhibitors in effective treatment of TNBC.Activation of Wnt pathway was assessed in four TNBC cell lines (BT-549, MDA-MB-231, HCC-1143 and HCC-1937), and the ER+ cell line MCF-7 using confocal microscopy and Western blot analysis of pathway components. Effectiveness of five different Wnt pathway inhibitors (iCRT-3, iCRT-5, iCRT-14, IWP-4 and XAV-939) on cell proliferation and apoptosis were tested in vitro. The inhibitory effects of iCRT-3 on canonical Wnt signaling in TNBC was evaluated by quantitative real-time RT-PCR analysis of Axin2 and dual-luciferase reporter assays. The effects of shRNA knockdown of SOX4 in combination with iCRT-3 and/or genistein treatments on cell proliferation, migration and invasion on BT-549 cells were also evaluated.Immunofluorescence staining of ?-catenin in TNBC cell lines showed both nuclear and cytoplasmic localization, indicating activation of Wnt pathway in TNBC cells. iCRT-3 was the most effective compound for inhibiting proliferation and antagonizing Wnt signaling in TNBC cells. In addition, treatment with iCRT-3 resulted in increased apoptosis in vitro. Knockdown of the Wnt pathway transcription factor, SOX4 in triple negative BT-549 cells resulted in decreased cell proliferation and migration, and combination treatment of iCRT-3 with SOX4 knockdown had a synergistic effect on inhibition of cell proliferation and induction of apoptosis.These data suggest that targeting SOX4 and/or the Wnt pathway could have therapeutic benefit for TNBC patients.

Dataset Information

Overexpression of ?-Arrestins inhibits proliferation and motility in triple negative breast cancer cells.

Publications

Overexpression of β-Arrestins inhibits proliferation and motility in triple negative breast cancer cells.

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