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The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
School of Life Sciences, University of Skövde, Skövde, Sweden.
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 1, article id 350Article in journal (Refereed) Published
Abstract [en]

Background: 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.

Methods: 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).

Results: 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).

Conclusions: 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.

Place, publisher, year, edition, pages
2012. Vol. 12, no 1, article id 350
Keywords [en]
Breast cancer, HER2, SLC25A43, S-phase
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-27546DOI: 10.1186/1471-2407-12-350ISI: 000309407100001PubMedID: 22883974Scopus ID: 2-s2.0-84864803696OAI: oai:DiVA.org:oru-27546DiVA, id: diva2:605084
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2017-12-06Bibliographically approved
In thesis
1. The mitochondrial protein SLC25A43 and it's possible role in HER2-positive breast cancer
Open this publication in new window or tab >>The mitochondrial protein SLC25A43 and it's possible role in HER2-positive breast cancer
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013
Series
Örebro Studies in Medicine, ISSN 1652-4063
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-26797 (URN)
Public defence
2013-01-25, Wilandersalen, Örebro universitetssjukus, Örebro, 13:15 (Swedish)
Opponent
Available from: 2013-01-08 Created: 2013-01-08 Last updated: 2017-10-17Bibliographically approved
2. Biological signature of HER2-positive breast cancer
Open this publication in new window or tab >>Biological signature of HER2-positive breast cancer
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human epidermal growth factor receptor 2 (HER2) overexpressing breast cancers (HER2+ breast cancer) are associated with an aggressive disease course. This thesis is focused on improving the understanding of the biological signature of HER2+ breast cancer.

In Paper I, we identified a common deletion spanning the SLC25A43 gene which codes for a mitochondrial transport protein. Loss of heterozygosity in this gene was confirmed in an extended cohort of HER2+ breast cancer and in other types of cancers. Protein expression analysis of SLC25A43using immunohistochemistry (IHC) in HER2+ breast cancers showed that tumours with negative or low expression of SLC25A43 had lower S-phase fraction compared to tumours with medium or high expression, indicating its possible role in cell proliferation. Absence of mutations in this gene in HER2+ breast cancers led to Paper II where DNA methylation in the SLC25A43 gene was interrogated using Pyrosequencing. HER2+ breast cancer with no deletion in the SLC25A43 gene showed higher methylation in the CpG island (CGI), suggesting methylation in the CGI as an alternate mechanism for SLC25A43 gene inactivation. Methylation in the CGI and in the adjacent shores of the SLC25A43 gene was associated with negative oestrogen receptor status and positive lymph node status. In Paper III, genome-wide DNA methylation analysis of HER2+ breast cancer and normal breast tissue revealed hypermethylation in HER2+ breast cancer affecting particularly the homeobox gene family when compared to normal. We identified a total of 73 candidate genes showing differential methylation in HER2+ breast cancer and external validation of gene expression in a selected group of these genes revealed lowered mean expression in HER2+ breast cancer, warranting future clinical studies of these candidate genes. In Paper IV, we investigated expression and localisation of phosphorylated (p) Akt and FOXO3a and FOXG1 in HER2+ breast cancer using IHC. Cytoplasmic expression of pFOXO3a was associated with sentinel node metastasis while cytoplasmic expression of FOXG1 was correlated to negative progesterone receptor status. This indicates the biological and prognostic value of these proteins in HER2+ breast cancer.

Thus, this thesis identified changes at the genetic, epigenetic and protein levels which add new information and improve our understanding of HER2+ breast cancer.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013. p. 61
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 90
Keywords
HER2+ breast cancer, SLC25A43, CpG island, DNA methylation, Homeobox genes, FOXO3a, FOXG1
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-28978 (URN)978-91-7668-941-7 (ISBN)
Public defence
2013-06-14, Wilandersalen, F-huset, Örebro universitetssjukhus, Södra Grev Rosengatan, Örebro, 11:00 (Swedish)
Opponent
Supervisors
Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2018-03-09Bibliographically approved

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Tina, ElisabetLindqvist, Breezy MalakkaranWingren, Sten

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