1 BMC Cancer 2012 Vol: 12(1):350. DOI: 10.1186/1471-2407-12-350

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

Overexpression 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. In 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). A 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). We 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.

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Figures
Figure 1: Protein expression of SLC24A43 in HER2-positive tumours on TMA. Staining of SLC25A43 is localised to the cytoplasm of the cells. Comparison of staining localisation and pattern between SLC25A43 and the mitochondrial inner membrane protein ATP5B in breast tumours (x40 Objective) (a). The four different levels of SLC24A43 expression in HER2-positive tumours used for scoring (x20 Objective) (b). Scale bar is showing 200 μm. Figure 2: Deletions at Xq24 in HER2-positive cancer. Tumour samples were analysed using whole-genome array to identify CNVs. Start and end points for the deletion found in 20 of 25 cases at Xq24. The position of SLC25A43 is marked blue on the X-axis. Figure 3: Boxplot of S-phase distribution and SLC24A43 protein expression. S-phase fraction in tumours with negative/low protein expression (n = 26) and medium/high expression (n = 45) of SLC25A43.
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References
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