MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis.
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 poo...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3739787?pdf=render |
| _version_ | 1818485359078539264 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | James W Antoon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T16:07:53Z |
| format | Article |
| id | doaj.art-8571bdcde50e4989b083c4eda4699a1e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T16:07:53Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8571bdcde50e4989b083c4eda4699a1e2022-12-22T01:42:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0188e6929110.1371/journal.pone.0069291MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis.James W AntoonElizabeth C MartinRongye LaiVirgilo A SalvoYan TangAshley M NitzchkeSteven ElliottSeung Yoon NamWei XiongLyndsay V RhodesBridgette Collins-BurowOdile DavidGuandi WangBin ShanBarbara S BeckmanKenneth P NephewMatthew E BurowEndocrine 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.http://europepmc.org/articles/PMC3739787?pdf=render |
| spellingShingle | 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 MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. PLoS ONE |
| title | MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. |
| title_full | MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. |
| title_fullStr | MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. |
| title_full_unstemmed | MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. |
| title_short | MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. |
| title_sort | mek5 erk5 signaling suppresses estrogen receptor expression and promotes hormone independent tumorigenesis |
| url | http://europepmc.org/articles/PMC3739787?pdf=render |
| work_keys_str_mv | AT jameswantoon mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT elizabethcmartin mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT rongyelai mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT virgiloasalvo mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT yantang mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT ashleymnitzchke mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT stevenelliott mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT seungyoonnam mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT weixiong mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT lyndsayvrhodes mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT bridgettecollinsburow mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT odiledavid mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT guandiwang mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT binshan mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT barbarasbeckman mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT kennethpnephew mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis AT mattheweburow mek5erk5signalingsuppressesestrogenreceptorexpressionandpromoteshormoneindependenttumorigenesis |