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Role of cell-cell adhesion in Profilin-1-dependent modulation of breast cancer cell proliferation

Zou, Li (2009) Role of cell-cell adhesion in Profilin-1-dependent modulation of breast cancer cell proliferation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zou, Liliz11@pitt.eduLIZ11
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoy, Parthapar19@pitt.eduPAR19
Committee MemberWells, Alanwellsa@upmc.eduAHW6
Committee MemberShroff, Sanjeevsshroff@pitt.eduSSHROFF
Committee MemberMonga, Satdarshan Psmonga@pitt.eduSMONGA
Date: 25 September 2009
Date Type: Completion
Defense Date: 14 April 2009
Approval Date: 25 September 2009
Submission Date: 19 May 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: breast cancer; cell adhesion; cell migration; cell proliferation; profilin; R-cadherin
Other ID:, etd-05192009-144306
Date Deposited: 10 Nov 2011 19:45
Last Modified: 19 Dec 2016 14:36


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