Oncotarget

Research Papers:

A class of genes in the HER2 regulon that is poised for transcription in breast cancer cell lines and expressed in human breast tumors

Farah B. Rahmatpanah _, Zhenyu Jia, Xin Chen, Jessica E. Char, Bozhao Men, Anna-Clara Franke, Frank E. Jones, Michael McClelland and Dan Mercola

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Oncotarget. 2015; 6:1286-1301. https://doi.org/10.18632/oncotarget.2676

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Abstract

Farah B. Rahmatpanah1, Zhenyu Jia1,4,5, Xin Chen1, Jessica E. Char1, Bozhao Men1, Anna-Clara Franke1, Frank E. Jones2, Michael McClelland1,3 and Dan Mercola1

1 Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA

2 Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA

3 Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA

4 Department of Statistics, University of Akron, Akron, Ohio, USA

5 Department of Family and Community Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA

Correspondence:

Dan Mercola, email:

Keywords: RNA polymerase II, promoter array, HER2, breast cancer, expression analysis, HER2 Regulon, chromatin immunoprecipitation, mammospheres, mammary stem cells, NANOG, SOX2, OCT3/4

Received: August 21, 2014 Accepted: November 04, 2014 Published: November 04, 2014

Abstract

HER2-positive breast cancer accounts for 25% of all cases and has a poor prognosis. Although progress has been made in understanding signal transduction, little is known of how HER2 achieves gene regulation. We performed whole genome expression analysis on a HER2+ and HER2- breast cancer cell lines and compared these results to expression in 812 primary tumors stratified by their HER2 expression level. Chip-on-chip with anti-RNA polymerase II was compared among breast cancer cell lines to identify genes that are potentially activated by HER2. The expression levels of these HER2-dependent POL II binding genes were determined for the 812 HER2+/- breast cancer tissues. Genes differentially expressed between HER2+/- cell lines were generally regulated in the same direction as in breast cancer tissues. We identified genes that had POLII binding in HER2+ cell lines, but without significant gene expression. Of 737 such genes “poised” for expression in cell lines, 113 genes were significantly differentially expressed in breast tumors in a HER2-dependent manner. Pathway analysis of these 113 genes revealed that a large group of genes were associated with stem cell and progenitor cell control as indicated by networks centered on NANOG, SOX2, OCT3/4. HER2 directs POL II binding to a large number of genes in breast cancer cells. A “poised” class of genes in HER2+ cell lines with POLII binding and low RNA expression but is differentially expressed in primary tumors, strongly suggests a role of the microenvironment and further suggests a role for stem cells proliferation in HER2-regulated breast cancer tissue.


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