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.
Highlights
Despite recent advances in endocrine therapy and the development of new agents, resistance remains a major obstacle in the treatment of breast cancer
Given the enhanced epithelial-to-mesenchymal transition (EMT)-associated changes found in our array data and our findings of an inverse correlation between ERK5 activation and estrogen receptor (ER)-a expression (Fig. 1B), we further investigated the ER-a signaling changes associated with MEK5 overexpression
While recent evidence indicates a role for mitogen activated protein kinases (MAPKs) signaling in cancer oncogenesis and metastasis, the role of the MEK5-ERK5 pathway in breast cancer progression remains poorly understood
Summary
Despite recent advances in endocrine therapy and the development of new agents, resistance remains a major obstacle in the treatment of breast cancer. The progression of cancer cells to a resistant phenotype is generally characterized by the acquisition of cellular or molecular changes that alter the response to therapeutic agents. Both acquired and de novo resistance occurs through enhanced cellular signaling cascades that circumvent estrogen receptor (ER)-dependent proliferation [1]. A better understanding of the mechanisms involved in the progression to endocrine resistance is critical for developing new targeted breast cancer therapies
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