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MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis.
- Source :
-
PloS one [PLoS One] 2013 Aug 09; Vol. 8 (8), pp. e69291. Date of Electronic Publication: 2013 Aug 09 (Print Publication: 2013). - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Antineoplastic Agents, Hormonal pharmacology
Breast Neoplasms metabolism
Breast Neoplasms pathology
Carcinogenesis genetics
Carcinogenesis metabolism
Carcinogenesis pathology
Carcinoma metabolism
Carcinoma pathology
Cell Line, Tumor
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Epithelial-Mesenchymal Transition genetics
Estradiol analogs & derivatives
Estradiol pharmacology
Estrogen Receptor alpha metabolism
Estrogens metabolism
Female
Fulvestrant
Gene Expression Profiling
Humans
MAP Kinase Kinase 5 metabolism
Mice
Mitogen-Activated Protein Kinase 7 antagonists & inhibitors
Mitogen-Activated Protein Kinase 7 metabolism
Neoplasms, Experimental
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Signal Transduction
Breast Neoplasms genetics
Carcinoma genetics
Estrogen Receptor alpha genetics
Gene Expression Regulation, Neoplastic
MAP Kinase Kinase 5 genetics
Mitogen-Activated Protein Kinase 7 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23950888
- Full Text :
- https://doi.org/10.1371/journal.pone.0069291