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DNA methylation pattern of the SLC25A43 gene in breast cancer
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
Örebro University, School of Medicine, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
2012 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 7, no 3, p. 300-306Article in journal (Refereed) Published
Abstract [en]

Solute carrier family 25A member 43 (SLC25A43) gene is a putative tumor suppressor gene that undergoes loss of heterozygosity (LOH) in human epidermal growth factor receptor 2 (HER2) positive breast cancer. Also, knockdown of SLC25A43 in cell lines influences cell turnover and metabolism. Absence of mutations in this gene in breast cancers prompted us to study methylation as an alternate mechanism for gene inactivation of this X encoded gene. Quantification of CpG site methylation using pyrosequencing was performed upstream of the SLC25A43 gene and at its 5' end in a cohort of breast tumor tissues (n = 80, HER2 positive or negative) with different SLC25A43 gene deletion status. Compared with control tissue, cancer tissues had lower levels of methylation at the 5' and 3' shores of the gene. Cancer tissues with no deletion in the SLC25A43 gene (Del(-)) had higher methylation in the CpG island (CGI) of the gene than cancers carrying the deletion (Del(+)). Methylation in the CGI of the SLC25A43 gene was negatively correlated with age at diagnosis. In HER2 positive breast cancer, ER negativity and lymph node positivity was associated with higher methylation in the CGI and in the adjacent shores of this gene. Our results suggest that methylation in the CGI of the SLC25A43 gene could be an alternate mechanism of gene silencing in the absence of LOH. Also, associations between site-specific methylation and clinicopathological parameters suggest that epigenetic changes in SLC25A43 gene could be of importance in breast carcinogenesis.

Place, publisher, year, edition, pages
Austin, USA: Landes Bioscience , 2012. Vol. 7, no 3, p. 300-306
Keywords [en]
Breast cancer, CpG island, CpG shore, gene inactivation, HER2 receptor, methylation, SLC25A43 gene
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-22553DOI: 10.4161/epi.7.3.19064ISI: 000301428800011PubMedID: 22430806Scopus ID: 2-s2.0-84858205498OAI: oai:DiVA.org:oru-22553DiVA, id: diva2:515829
Funder
Swedish Cancer Society
Note

Funding Agencies:

Nyckelfonden Örebro, Sweden 

Lions Cancer Foundation, Sweden 

Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2017-12-07Bibliographically approved
In thesis
1. 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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Lindqvist, Breezy MalakkaranFarkas, Sanja A.Wingren, StenNilsson, Torbjörn K.

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Epigenetics
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