Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells.
Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards t...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4016211?pdf=render |
| _version_ | 1811231821393821696 |
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| author | Mateusz Opyrchal Jeffrey L Salisbury Shuya Zhang James McCubrey John Hawse Mattew P Goetz Gwen A Lomberk Tufia Haddad Amy Degnim Carol Lange James N Ingle Evanthia Galanis Antonino B D'Assoro |
| author_facet | Mateusz Opyrchal Jeffrey L Salisbury Shuya Zhang James McCubrey John Hawse Mattew P Goetz Gwen A Lomberk Tufia Haddad Amy Degnim Carol Lange James N Ingle Evanthia Galanis Antonino B D'Assoro |
| author_sort | Mateusz Opyrchal |
| collection | DOAJ |
| description | Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the 'cross-talk' between ERα and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERα+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERα signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in initially ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients. |
| first_indexed | 2024-04-12T10:52:31Z |
| format | Article |
| id | doaj.art-c7da98dd6ce74f7c926be89deef9be93 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T10:52:31Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c7da98dd6ce74f7c926be89deef9be932022-12-22T03:36:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9699510.1371/journal.pone.0096995Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells.Mateusz OpyrchalJeffrey L SalisburyShuya ZhangJames McCubreyJohn HawseMattew P GoetzGwen A LomberkTufia HaddadAmy DegnimCarol LangeJames N IngleEvanthia GalanisAntonino B D'AssoroDevelopment of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the 'cross-talk' between ERα and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERα+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERα signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in initially ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients.http://europepmc.org/articles/PMC4016211?pdf=render |
| spellingShingle | Mateusz Opyrchal Jeffrey L Salisbury Shuya Zhang James McCubrey John Hawse Mattew P Goetz Gwen A Lomberk Tufia Haddad Amy Degnim Carol Lange James N Ingle Evanthia Galanis Antonino B D'Assoro Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. PLoS ONE |
| title | Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. |
| title_full | Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. |
| title_fullStr | Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. |
| title_full_unstemmed | Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. |
| title_short | Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. |
| title_sort | aurora a mitotic kinase induces endocrine resistance through down regulation of erα expression in initially erα breast cancer cells |
| url | http://europepmc.org/articles/PMC4016211?pdf=render |
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