Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells
Background The membrane cytoskeletal crosslinker, ezrin, a member of the ERM family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. Our group previously showed that ezrin acts co-operatively with the non-receptor tyros...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BioMed Central Ltd.
2012
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| Online Access: | http://hdl.handle.net/1721.1/71715 |
| _version_ | 1826216906857644032 |
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| author | Mak, Hannah Naba, Alexandra Varma, Sonal Schick, Colleen Day, Andrew SenGupta, Sandip K Arpin, Monique Elliott, Bruce E |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Mak, Hannah Naba, Alexandra Varma, Sonal Schick, Colleen Day, Andrew SenGupta, Sandip K Arpin, Monique Elliott, Bruce E |
| author_sort | Mak, Hannah |
| collection | MIT |
| description | Background The membrane cytoskeletal crosslinker, ezrin, a member of the ERM family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. Our group previously showed that ezrin acts co-operatively with the non-receptor tyrosine kinase, Src, in deregulation of cell-cell contacts and scattering of epithelial cells. In particular, ezrin phosphorylation on Y477 by Src is specific to ezrin within the ERM family, and is required for HGF-induced scattering of epithelial cells. We therefore sought to examine the role of Y477 phosphorylation in ezrin on tumor progression. Methods Using a highly metastatic mouse mammary carcinoma cell line (AC2M2), we tested the effect of over-expressing a non-phosphorylatable form of ezrin (Y477F) on invasive colony growth in 3-dimensional Matrigel cultures, and on local invasion and metastasis in an orthotopic engraftment model. Results AC2M2 cells over-expressing Y477F ezrin exhibited delayed migration in vitro, and cohesive round colonies in 3-dimensional Matrigel cultures, compared to control cells that formed invasive colonies with branching chains of cells and numerous actin-rich protrusions. Moreover, over-expression of Y477F ezrin inhibits local tumor invasion in vivo. Whereas orthotopically injected wild type AC2M2 tumor cells were found to infiltrate into the abdominal wall and visceral organs within three weeks, tumors expressing Y477F ezrin remained circumscribed, with little invasion into the surrounding stroma and abdominal wall. Additionally, Y477F ezrin reduces the number of lung metastatic lesions. Conclusions Our study implicates a role of Y477 ezrin, which is phosphorylated by Src, in regulating local invasion and metastasis of breast carcinoma cells, and provides a clinically relevant model for assessing the Src/ezrin pathway as a potential prognostic/predictive marker or treatment target for invasive human breast cancer. |
| first_indexed | 2024-09-23T16:55:21Z |
| format | Article |
| id | mit-1721.1/71715 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:55:21Z |
| publishDate | 2012 |
| publisher | BioMed Central Ltd. |
| record_format | dspace |
| spelling | mit-1721.1/717152022-10-03T09:09:06Z Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells Mak, Hannah Naba, Alexandra Varma, Sonal Schick, Colleen Day, Andrew SenGupta, Sandip K Arpin, Monique Elliott, Bruce E Koch Institute for Integrative Cancer Research at MIT Naba, Alexandra Background The membrane cytoskeletal crosslinker, ezrin, a member of the ERM family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. Our group previously showed that ezrin acts co-operatively with the non-receptor tyrosine kinase, Src, in deregulation of cell-cell contacts and scattering of epithelial cells. In particular, ezrin phosphorylation on Y477 by Src is specific to ezrin within the ERM family, and is required for HGF-induced scattering of epithelial cells. We therefore sought to examine the role of Y477 phosphorylation in ezrin on tumor progression. Methods Using a highly metastatic mouse mammary carcinoma cell line (AC2M2), we tested the effect of over-expressing a non-phosphorylatable form of ezrin (Y477F) on invasive colony growth in 3-dimensional Matrigel cultures, and on local invasion and metastasis in an orthotopic engraftment model. Results AC2M2 cells over-expressing Y477F ezrin exhibited delayed migration in vitro, and cohesive round colonies in 3-dimensional Matrigel cultures, compared to control cells that formed invasive colonies with branching chains of cells and numerous actin-rich protrusions. Moreover, over-expression of Y477F ezrin inhibits local tumor invasion in vivo. Whereas orthotopically injected wild type AC2M2 tumor cells were found to infiltrate into the abdominal wall and visceral organs within three weeks, tumors expressing Y477F ezrin remained circumscribed, with little invasion into the surrounding stroma and abdominal wall. Additionally, Y477F ezrin reduces the number of lung metastatic lesions. Conclusions Our study implicates a role of Y477 ezrin, which is phosphorylated by Src, in regulating local invasion and metastasis of breast carcinoma cells, and provides a clinically relevant model for assessing the Src/ezrin pathway as a potential prognostic/predictive marker or treatment target for invasive human breast cancer. Canadian Breast Cancer Research Alliance (BEE, 017374) Canadian Institutes of Health Research (BEE, 102644) Physicians Society Inc. Association pour le développement de la recherche sur le cancer (France) 2012-07-19T20:27:19Z 2012-07-19T20:27:19Z 2012-03 2011-08 2012-06-11T11:08:37Z Article http://purl.org/eprint/type/JournalArticle 1471-2407 http://hdl.handle.net/1721.1/71715 Mak, Hannah Y. et al. “Ezrin Phosphorylation on Tyrosine 477 Regulates Invasion and Metastasis of Breast Cancer Cells.” BMC Cancer 12.1 (2012): 82. Web. en http://dx.doi.org/10.1186/1471-2407-12-82 BMC Cancer Creative Commons Attribution http://creativecommons.org/licenses/by/2.0 Hannah Mak et al.; licensee BioMed Central Ltd. application/pdf BioMed Central Ltd. BioMed Central Ltd |
| spellingShingle | Mak, Hannah Naba, Alexandra Varma, Sonal Schick, Colleen Day, Andrew SenGupta, Sandip K Arpin, Monique Elliott, Bruce E Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells |
| title | Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells |
| title_full | Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells |
| title_fullStr | Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells |
| title_full_unstemmed | Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells |
| title_short | Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells |
| title_sort | ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells |
| url | http://hdl.handle.net/1721.1/71715 |
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