Hallmarks of progression of epithelial-derived tumors include downregulation of cell-cell adhesion, dysregulated cell proliferation, increased resistance to apoptosis and acquisition of motile and invasive phenotype. Profilin-1 (Pfn1) is a ubiquitously expressed actin-binding protein which is required for proliferation and migration of most normal cells, yet its expression is significantly downregulated in various types of adenocarcinoma including those originating in breast, pancreas and liver. Tumor-suppressive action of Pfn1 on breast cancer cells has also been previously documented in the literature. The present study shows that loss of Pfn1 expression in normal human mammary epithelial cells leads to junctional delocalization of E-cadherin with a concomitant reduction in cell-cell adhesion, reduced cell-matrix adhesion, increased cell proliferation and a hypermotile phenotype. These findings may provide a possible insight on why Pfn1 expression is downregulated in breast cancer cells. Using MDA-MB-231 as a model system for mesenchymal breast cancer cell type, we further show that overexpression of Pfn1 can restore adherence junctions and phenotypic reversion to an epithelioid-type through junctional stabilization of an endogenously expressed cadherin molecule. Pfn1 overexpression in MDA-MB-231 cells causes cell-cycle arrest at G1, inhibition in proliferation in vitro and tumor growth in vivo. Pfn1-induced growth inhibition of MDA-MB-231 cells is partly mediated by upregulation of p27kip1 (a CDK inhibitor) in cell-cell adhesion-dependent manner. We finally show that Pfn1 overexpression also sensitizes MDA-MB-231 cells to apoptosis suggesting the survival of breast cancer cells can also be modulated Pfn1. Taken together, these findings highlight for the first time mechanistic insights underlying some of the tumor-suppressive properties of Pfn1.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-05192009-144306 |
| Date | 25 September 2009 |
| Creators | Zou, Li |
| Contributors | Partha Roy, Sanjeev Shroff, Satdarshan P. Monga, Alan Wells |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-05192009-144306/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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