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Evaluation of gene expression data from cybrids and tumours highlights elevated NDRG1-driven proliferation in triplenegative breast cancer

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Original languageEnglish
JournalBreast Cancer: Basic and Clinical Research
Early online date22 Jun 2020
DOIs
Publication statusE-pub ahead of print - 22 Jun 2020

Abstract

Background. Triple-negative breast cancer is an aggressive type of breast cancer with high risk of recurrence. It is still poorly understood and lacks any targeted therapy, which makes it difficult to treat. Thus, it is important to understand underlying mechanisms and pathways that are dysregulated in triple-negative breast cancer.
Methods. To investigate the role of mitochondria in triple-negative breast cancer progression, we analysed previously reported gene expression data from triple-negative breast cancer cybrids with SUM-159 as the nuclear donor cell and SUM-159 or A1N4 (c-SUM-159, c-A1N4) as the mitochondrial donor cells and with 143B as the nuclear donor cell and MCF-10A or MDA-MB-231 (c-
MCF-10A, c-MDA-MB-231) as the mitochondrial donor cells. The role of potential biomarkers in cell proliferation and migration was examined in SUM-159 and MDA-MB-231 cells using sulforhodamine B and wound healing assays.
Results. Rank product analysis of cybrid gene expression data identified 149 genes which were significantly up-regulated in the cybrids with mitochondria from the cancer cell line. Analysis of previously reported breast tumour gene expression datasets confirmed 9 out of the 149 genes were amplified, up-regulated or down-regulated in more than 10% of the patients. The genes included NDRG1, PVT1 and EXT1, which are co-located in cytoband 8q24, which is frequently amplified in breast cancer. NDRG1 showed the largest down-regulation in the cybrids with benign mitochondria and was associated with poor prognosis in a breast cancer clinical dataset. Knockdown of NDRG1
expression significantly decreased proliferation of SUM-159 triple-negative breast cancer cells.
Conclusions. These results indicate that mitochondria-regulated nuclear gene expression helps breast cancer cells survive and proliferate, consistent with previous work focusing on a src gene signature which is mitochondria regulated and drives malignancy in breast cancer cybrids. This is the first study to show that mitochondria in triple-negative breast cancer mediate significant upregulation of a number of genes, and silencing of NDRG1 leads to significant reduction in proliferation.

    Research areas

  • NDRG1, breast cancer, cybrids

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