The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors

Abstract

BackgroundOverexpression of the human epidermal growth factor receptor (HER) 2 is associated with poor prognosis and shortened survival in breast cancer patients. HER2 is a potent activator of several signaling pathways that support cell survival, proliferation and metabolism. In HER2-positive breast cancer there are most likely unexplored proteins that act directly or indirectly downstream of well established pathways and take part in tumor development and treatment response.MethodsIn order to identify novel copy number variations (CNVs) in HER2-positive breast cancer whole-genome single nucleotide polymorphism (SNP) arrays were used. A PCR-based loss of heterozygosis (LOH) assay was conducted to verify presence of deletion in HER2-positive breast cancer cases but also in HER2 negative breast cancers, cervical cancers and lung cancers. Screening for mutations was performed using single-strand conformation polymorphism (SSCP) followed by PCR sequencing. Protein expression was evaluated with immunohistochemistry (IHC).ResultsA common deletion at chromosome Xq24 was found in 80% of the cases. This locus harbors the gene solute carrier (SLC) family 25A member 43 (SLC25A43) encoding for a mitochondrial transport protein. The LOH assay revealed presence of SLC25A43 deletion in HER2-positive (48%), HER2-negative (9%), cervical (42%) and lung (67%) cancers. HER2-positive tumors with negative or low SLC25A43 protein expression had significantly lower S-phase fraction compared to tumors with medium or high expression (P = 0.024).ConclusionsWe have found deletion in the SLC25A43 gene to be a common event in HER2-positive breast cancer as well as in other cancers. In addition, the SLC25A43 protein expression was shown to be related to S-phase fraction in HER2-positive breast cancer. Our results indicate a possible role of SLC25A43 in HER2-positive breast cancer and support the hypothesis of altered mitochondrial function in cancer.

The mitochondrial transport protein SLC25A43 affects drug efficacy and drug-induced cell cycle arrest in breast cancer cell lines

“…We previously demonstrated a common loss of the mitochondrial gene SLC25A43 in HER2-positive breast cancer (28). We further showed that HER2-positive breast tumours with a lower expression of SLC25A43 also have a lower S phase fraction.…”

“…However, the complete function of SLC25A43 along with the substrate carried by this membrane transporter remains unknown. We noted that lower expression of SLC25A43 in the tumours correlated significantly with a lower S phase fraction in HER2-positive breast cancer (28). …”

“…We previously described novel findings of a commonly deleted gene in HER2-positive breast cancer (28). This gene encodes the mitochondrial inner membrane solute carrier protein SLC25A43.…”

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer

“…These numbers were then transformed to z-scores in a gene-wise manner, reordered according to the dendrogram in (A), and represented as a heatmap. As a further control, we chose and validated 3 more genes whose expression has been correlated with breast cancer hormone and drug response, namely solute carrier 25A43 (SLC25A43), PGR, and solute carrier 7AB (SLC7A8) (15,20,57,58). PGR, progesterone receptor; qPCR, quantitative polymerase chain reaction.…”

Assessment of correlation between pre-miRNA-1757 polymorphism and chicken performance traits

“…The miR-1757 gene as an intronic miRNA is located in intron 1 of the solute carrier (SLC) family 25A member 43 (SLC25A43) host gene on chromosome 4. SLC25A43 encodes for a mitochondrial transport protein, and may be involved in cell turnover, metabolism, and cell proliferation , Tina et al, 2012. Intronic miRNAs have been reported to play an antagonistic or synergetic role with their host genes (Gao et al, 2012).…”