MEK5/ERK5 Signaling Suppresses Estrogen Receptor Expression and Promotes Hormone-Independent Tumorigenesis

James W. Antoon, Elizabeth C. Martin, Rongye Lai, Virgilo A. Salvo, Yan Tang, Ashley M. Nitzchke, Steven Elliott, Seung Yoon Nam, Wei Xiong, Lyndsay V. Rhodes, Bridgette Collins-Burow, Odile David, Guandi Wang, Bin Shan, Barbara S. Beckman, Kenneth P. Nephew, Matthew E. Burow

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(-), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.

Original languageEnglish (US)
Article numbere69291
JournalPloS one
Volume8
Issue number8
DOIs
StatePublished - Aug 9 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Antoon, J. W., Martin, E. C., Lai, R., Salvo, V. A., Tang, Y., Nitzchke, A. M., Elliott, S., Nam, S. Y., Xiong, W., Rhodes, L. V., Collins-Burow, B., David, O., Wang, G., Shan, B., Beckman, B. S., Nephew, K. P., & Burow, M. E. (2013). MEK5/ERK5 Signaling Suppresses Estrogen Receptor Expression and Promotes Hormone-Independent Tumorigenesis. PloS one, 8(8), [e69291]. https://doi.org/10.1371/journal.pone.0069291