Antoon, James W.Martin, Elizabeth C.Lai, RongyeSalvo, Virgilo A.Tang, YanNitzchke, Ashley M.Elliott, StevenNam, Seung YoonXiong, WeiRhodes, Lyndsay V.Collins-Burow, BridgetteDavid, OdileWang, GuandiShan, BinBeckman, Barbara S.Nephew, Kenneth P.Burow, Matthew E.2025-05-022025-05-022013-08-09Antoon JW, Martin EC, Lai R, et al. MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. PLoS One. 2013;8(8):e69291. Published 2013 Aug 9. doi:10.1371/journal.pone.0069291https://hdl.handle.net/1805/47633Endocrine 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.en-USAttribution 4.0 InternationalBreast neoplasmsCarcinogenesisCarcinomaEstradiolMitogen-activated protein kinase 7Article