| Overexpression of RhoA induces preneoplastic transformation of primary mammary epithelial cells. | |
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MedLine Citation:
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PMID: 19147561 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions, including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably used immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMEC). We show here that ectopic expression of wild-type (WT) RhoA as well as a constitutively active RhoA mutant (G14V) in two independent primary hMEC strains led to their immortalization and preneoplastic transformation. These cells have continued to grow over 300 population doublings (PD) with no signs of senescence, whereas cells expressing the vector or dominant-negative RhoA mutant (T19N) senesced after 20 PDs. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well-known Rho effectors including Rho kinase, PKN, mDia1, and mDia2, was also capable of immortalizing hMECs. Notably, similar to parental normal cells, Rho-immortalized cells have WT p53 and intact G(1) cell cycle arrest on Adriamycin treatment. Rho-immortalized cells were anchorage dependent and were unable to form tumors when implanted in nude mice. Lastly, microarray expression profiling of Rho-immortalized versus parental cells showed altered expression of several genes previously implicated in immortalization and breast cancer progression. Taken together, these results show that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked to cellular transformation and breast cancer. |
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Authors:
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Xiangshan Zhao; Lin Lu; Nidhi Pokhriyal; Hui Ma; Lei Duan; Simon Lin; Nadereh Jafari; Hamid Band; Vimla Band |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Cancer research Volume: 69 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2009-01-16 Completed Date: 2009-02-20 Revised Date: 2011-03-22 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 483-91 Citation Subset: IM |
Affiliation:
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Department of Genetics, Eppley Institute for Cancer and Allied Diseases and UNMC-Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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metabolism Animals Breast Neoplasms / enzymology*, pathology Cell Transformation, Neoplastic / metabolism*, pathology Female Humans Mammary Glands, Human / enzymology*, pathology Mice Mice, Nude Precancerous Conditions / enzymology*, pathology Protein Kinase C / metabolism Telomerase / metabolism rho-Associated Kinases / metabolism rhoA GTP-Binding Protein / biosynthesis* |
| Grant Support | |
ID/Acronym/Agency:
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CA105489/CA/NCI NIH HHS; CA116552/CA/NCI NIH HHS; CA87986/CA/NCI NIH HHS; CA94143/CA/NCI NIH HHS; CA96844/CA/NCI NIH HHS; CA99163/CA/NCI NIH HHS; CA99900/CA/NCI NIH HHS; R01 CA087986-01/CA/NCI NIH HHS; R01 CA087986-02/CA/NCI NIH HHS; R01 CA087986-03/CA/NCI NIH HHS; R01 CA087986-04/CA/NCI NIH HHS; R01 CA087986-05/CA/NCI NIH HHS; R01 CA087986-06/CA/NCI NIH HHS; R01 CA087986-07/CA/NCI NIH HHS; R01 CA087986-08/CA/NCI NIH HHS; R01 CA087986-09/CA/NCI NIH HHS; R01 CA087986-10/CA/NCI NIH HHS; R01 CA087986-11/CA/NCI NIH HHS; R01 CA087986-12/CA/NCI NIH HHS; R01 CA094143-01A1/CA/NCI NIH HHS; R01 CA094143-02/CA/NCI NIH HHS; R01 CA094143-03/CA/NCI NIH HHS; R01 CA094143-04/CA/NCI NIH HHS; R01 CA094143-05/CA/NCI NIH HHS; R01 CA094143-06/CA/NCI NIH HHS; R01 CA096844-01/CA/NCI NIH HHS; R01 CA096844-02/CA/NCI NIH HHS; R01 CA096844-03/CA/NCI NIH HHS; R01 CA096844-04/CA/NCI NIH HHS; R01 CA096844-05/CA/NCI NIH HHS; R01 CA096844-06/CA/NCI NIH HHS; R01 CA096844-07/CA/NCI NIH HHS; R01 CA096844-08/CA/NCI NIH HHS; R01 CA099163-01/CA/NCI NIH HHS; R01 CA099163-02/CA/NCI NIH HHS; R01 CA099163-03/CA/NCI NIH HHS; R01 CA099163-03S1/CA/NCI NIH HHS; R01 CA099163-04/CA/NCI NIH HHS; R01 CA099163-05/CA/NCI NIH HHS; R01 CA099163-06/CA/NCI NIH HHS; R01 CA099163-07/CA/NCI NIH HHS; R01 CA099163-08/CA/NCI NIH HHS; R01 CA099163-09/CA/NCI NIH HHS; R01 CA099900-01/CA/NCI NIH HHS; R01 CA099900-02/CA/NCI NIH HHS; R01 CA099900-03/CA/NCI NIH HHS; R01 CA099900-04/CA/NCI NIH HHS; R01 CA099900-05/CA/NCI NIH HHS; R01 CA099900-06/CA/NCI NIH HHS; R01 CA099900-07/CA/NCI NIH HHS; R01 CA105489-01/CA/NCI NIH HHS; R01 CA105489-02/CA/NCI NIH HHS; R01 CA105489-03/CA/NCI NIH HHS; R01 CA105489-04/CA/NCI NIH HHS; R01 CA105489-05/CA/NCI NIH HHS; R01 CA105489-06/CA/NCI NIH HHS; R01 CA116552-01A2/CA/NCI NIH HHS; R01 CA116552-02/CA/NCI NIH HHS; R01 CA116552-03/CA/NCI NIH HHS; R01 CA116552-04/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/DIAPH1 protein, human; 124671-05-2/RHOA protein, human; EC 2.7.1.-/protein kinase N; EC 2.7.11.1/rho-Associated Kinases; EC 2.7.11.13/Protein Kinase C; EC 2.7.7.49/Telomerase; EC 3.6.5.2/rhoA GTP-Binding Protein |
| Comments/Corrections | |
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