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The mitochondrial protein SLC25A43 and it's possible role in HER2-positive breast cancer
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
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: urn:nbn:se:oru:diva-26797OAI: oai:DiVA.org:oru-26797DiVA, id: diva2:583445
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
List of papers
1. The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors
Open this publication in new window or tab >>The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors
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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.

Keywords
Breast cancer, HER2, SLC25A43, S-phase
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-27546 (URN)10.1186/1471-2407-12-350 (DOI)000309407100001 ()22883974 (PubMedID)2-s2.0-84864803696 (Scopus ID)
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2017-12-06Bibliographically approved
2. Mitochondrial regulation of cell proliferation through SLC25A43 inHER2-positive breast cancer cells in vitro
Open this publication in new window or tab >>Mitochondrial regulation of cell proliferation through SLC25A43 inHER2-positive breast cancer cells in vitro
(English)Article in journal (Refereed) Submitted
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine; Oncology
Identifiers
urn:nbn:se:oru:diva-27548 (URN)
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2017-10-17Bibliographically approved
3. The mitochondrial transport protein SLC25A43 affects drug efficacy and drug-induced cell cycle arrest in breast cancer cell lines
Open this publication in new window or tab >>The mitochondrial transport protein SLC25A43 affects drug efficacy and drug-induced cell cycle arrest in breast cancer cell lines
2013 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 29, no 4, p. 1268-Article in journal (Refereed) Published
Abstract [en]

The mitochondria have been identified as key players of apoptosis, cell proliferation and cell cycle regulation. However, the role of mitochondria in breast cancer and treatment failure remains unclear. We have previously shown a common deletion of the gene SLC25A43 in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This gene is coding for a mitochondrial inner membrane transporter and, to date, little is known about the function of this protein. We have also found that low protein expression of SLC25A43 significantly correlates with a lower S phase fraction in HER2-positive breast cancer. The aim of this study was to investigate whether knockdown (KD) of SLC25A43 could have an effect on the cytotoxicity of different cytostatic drugs using MCF10A, MCF7 and BT-474 cells. Following siRNA-mediated KD of SLC25A43, one non-malignant and two breast cancer cell lines were exposed to the anthracycline epirubicin or the taxane paclitaxel. The HER2-positive breast cancer cells were also exposed to the targeted therapy trastuzumab and dual exposure to trastuzumab and paclitaxel. We found that KD of SLC25A43 resulted in a decreased cytotoxic effect of paclitaxel in the two cancer cell lines (P<0.05). Further analysis of cell cycle phase distribution showed that KD increased the paclitaxel-induced G2/M block in these two cell lines (P<0.05). KD of SLC25A43 also reduced the inhibitory effect of trastuzumab on cell proliferation in the HER2-positive cancer cell line BT-474 (P<0.05), and the drug-induced G0/G1 block (P<0.05). Moreover, SLC25A43 influenced the percentage of Ki-67-positive cells. Our findings demonstrate that the mitochondrial protein SLC25A43 affects drug efficacy and cell cycle regulation following drug exposure in breast cancer cell lines.

National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-27547 (URN)10.3892/or.2013.2247 (DOI)000316510600002 ()23354756 (PubMedID)
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2018-08-29Bibliographically approved
4. Regulation of cell proliferation and recurrence-free survival in HER2-positive breast cancer through SLC25A43 and p27
Open this publication in new window or tab >>Regulation of cell proliferation and recurrence-free survival in HER2-positive breast cancer through SLC25A43 and p27
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine; Oncology
Identifiers
urn:nbn:se:oru:diva-27550 (URN)
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2017-10-17Bibliographically approved

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Gabrielson, Marike

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