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Research Note

Abnormal expression of ATP1A1 and ATP1A2 in breast cancer

[version 1; peer review: 2 approved]
PUBLISHED 05 Jan 2017
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Abstract

Breast cancer is the first in incidence and the second in death among all solid tumors occurring in women. The identification of molecular genetic abnormalities in breast cancer is important to improve the results of treatment. In the present study, we analyzed microarray data of breast cancer expression profiling (NCBI GEO database, accession GSE65194), focusing on Na+/K+-ATPase coding genes. We found overexpression of the ATP1A1 and down-regulation of the ATP1A2. We expect that our research could help to improve the understanding of predictive and prognostic features of breast cancer.

Keywords

breast cancer, Na+/K+-ATPase, gene expression, abnormality, ATP1A1, ATP1A2

Introduction

Breast cancer is one of the most common and deadly female solid tumors1. According to reports from Perou et al.2, further confirmed by other investigators3,4, breast cancer is a highly molecularly heterogeneous disease. The identification of molecular genetic abnormalities in breast cancer is important to improve the results of treatment and, for instance, to reveal new targets for specific therapies. Recent studies based on original retrospective analysis of digitalis use in breast cancer patients have demonstrated the anticancer effect of cardiac glycosides5 that directly inhibit Na+/K+-ATPase (NKA) activity. NKA signaling functions after interaction with cardiac glycosides were also shown6. It seems rational that expression of NKA might influence breast cancer prognosis.

NKA is a significant integral membrane protein. NKA’s main function is the creation and maintenance of electrochemical gradients for sodium and potassium ions in the living cell. These gradients have critical importance for control of cell volume, osmolarity and resting potential7,8. The minimal functional NKA consists of two associated alpha- and beta- subunits. The catalytic alpha-subunit is responsible for conversion of ATP energy to transport of Na+ and K+ across cell membranes and has ATP and cardiac glycosides binding sites. It may be present in human tissues in four different isoforms (α1, α2, α3, α4 – found only in testicles). The beta-subunit is responsible for delivery and insertion of alpha one in cell membranes and has three distinct isoforms in humans (β1, β2, β3)810. NKA subunits are variably expressed in different human tissues11. Changes in the relative expression between different isoforms are associated with a number of pathological processes including malignant transformation12,13. Both down- and up-regulation of alpha- and beta- subunits were shown in solid tumors of different origin1419.

In the present study, we analyzed public breast cancer expression profiles made using Affymetrix Human Genome U133 Plus 2.0 Array (NCBI GEO database20, accession GSE65194) for the expression of alpha subunits of NKA. We found abnormalities in ATP1A1 (coding α1-subunit) and ATP1A2 (coding α2-subunit) expression (Table 1) in breast cancer samples relative to their expression in normal breast tissue. ATP1A1 was overexpressed approximately 1.5 times in all groups of breast cancer samples (p<0.05). Coincidently, ATP1A2 expression decreased by more than 2 times (p<0.05). There were no differences observed in the expression of ATP1A3 (coding α3-subunit).

Table 1. NKA genes expression in breast cancer samples relative to normal breast tissue.

Breast cancer
group
Lum ALum BHer2TNBC
GeneRelative expression/(ANOVA P-value)
ATP1A11.53
(0.009016)
1.38
(0.04454)
1.66
(0.005926)
1.44
(0.015725)
ATP1A2 -2.49
(1.85·10-07)
-2.52
(8.50·10-09)
-2.78
(5.48·10-08)
-2.87
(2.08·10-11)
ATP1A3 -1.05
(0.429089)
1.03
(0.308298)
-1.04
(0.768041)
-1.04
(0.527878)

Methods

Preanalytical procedures consisted of a robust multichip analysis (RMA) algorithm21, including background correction, probe set signal integration, and quantile normalization. For this purpose, we used Expression Console 1.4 software (Affymetrix, Inc. USA). We utilized Transcriptome Analysis Console 3.0 software (Affymetrix, Inc. USA) to analyze the obtained CHP files and to detect differentially expressed genes using one-way between subjects ANOVA. Array data for 41 triple negative samples (TNBC group), 30 Her2-positive (Her2 group), 30 Luminal B (Lum B group), 29 Luminal A (Lum A group) breast cancer samples and 11 normal breast tissue samples were investigated.

Conclusions

Using a public microarray dataset we found abnormalities in the expression of ATP1A1 and ATP1A2 in breast cancer samples. This may correlate with digitalis anticancer activity, but requires additional research. We expect that our research could help to improve the understanding of predictive and prognostic features of breast cancer.

Data and software availability

Raw data for Table 1 are available at:

https://www.ncbi.nlm.nih.gov/geo/download/?acc=GSE65194&format=file22.

Expression Console 1.4 software and Transcriptome Analysis Console 3.0 software (Affymetrix, Inc. USA) are available after free customer registration at:

http://www.affymetrix.com/support/technical/software_downloads.affx.

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Bogdanov A, Moiseenko FV and Dubina M. Abnormal expression of ATP1A1 and ATP1A2 in breast cancer [version 1; peer review: 2 approved]. F1000Research 2017, 6:10 (https://doi.org/10.12688/f1000research.10481.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 05 Jan 2017
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Reviewer Report 10 May 2017
Jen-Tsan Ashley Chi, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27708, USA 
Approved
VIEWS 12
I think the analysis is appropriate to examine the relative expression of the ATP1A1 and ATP1A2 among different breast cancer cells. The data analysis is standard and appropriate. One helpful thing is to validate the findings in other breast cancer ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Chi JTA. Reviewer Report For: Abnormal expression of ATP1A1 and ATP1A2 in breast cancer [version 1; peer review: 2 approved]. F1000Research 2017, 6:10 (https://doi.org/10.5256/f1000research.11294.r21728)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 21 Feb 2017
Mikhail Fedyanin, Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation 
Approved
VIEWS 13
Over the past years several papers were published concerning prognostic role of ATP1A1 expression in hepatocellular carcinoma, lung cancer, and esophageal cancer. The authors of the present study show that increased expression of ATP1A1 observed at all breast cancer phenotypes ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Fedyanin M. Reviewer Report For: Abnormal expression of ATP1A1 and ATP1A2 in breast cancer [version 1; peer review: 2 approved]. F1000Research 2017, 6:10 (https://doi.org/10.5256/f1000research.11294.r20402)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 05 Jan 2017
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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