Panchapakesa, Vaishnavi Rajendran
(2006)
Effects of functional perturbations of profilin on breast cancer cell migration and invasion.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Breast cancer, one of the most common types of cancer among women, is now the second leading cause of cancer deaths after lung cancer. Since a majority of cancer deaths are due to metastasis of breast tumor cells to distant organs, understanding tumor cell invasion and metastasis at a molecular level will help us in developing therapeutics that will improve the quality of life of breast cancer patients. Cell migration, an integral component of tumor invasion and metastasis, is regulated by the assembly and disassembly of actin cytoskeleton, which involves the coordinated action of several classes of actin binding proteins. It has been shown previously that there is reduced expression of profilin 1 (Pfn1- an ubiquitously expressed actin binding protein) in invasive breast cancer cells. Pfn1 is now considered as a tumor-suppressor protein based on its ability to restrict the growth and tumorigenesis of breast cancer cells when overexpressed. Besides actin, Pfn1 also binds to several families of proline-rich ligands and these interactions have been implicated in several cellular processes including actin assembly, endocytosis and gene transcription. We have previously shown that overexpression of Pfn1 reduces the migration of BT474, a ductal carcinoma breast cancer cell line. The aim of the present work is to determine whether overexpression or selective inhibition of ligand binding of Pfn1 alter the migration and invasion of metastatic breast cancer cells. Specifically, we have studied how stable overexpression of Pfn1 and its mutant forms that are selectively impaired in binding to either actin or proline-rich ligands affect the migration and invasion of MDA-MB-231, a highly metastatic breast cancer cell line. We show that functional perturbation of Pfn1 affects the F-actin content in MDA-MB-231 cells. Specifically, Pfn1 overexpression stimulates actin polymerization, whereas expression of an actin-binding deficient mutant of Pfn1 decreases the overall level of polymerized actin in MDA-MB-231 cells. Increased focal adhesion formation in MDA-MB-231 cells as a result of Pfn1 overexpression appears to require a functional actin-binding site of Pfn1. We show that cell migration and invasion in response to chemotactic stimulus are inhibited when either fully functional or mutant forms of Pfn1 are expressed in these cells. Finally, we demonstrate that perturbation of Pfn1 affects the secretion of matrix-metalloproteinases (enzymes that are important for matrix degradation during cell invasion) by MDA-MB-231 cells.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
27 September 2006 |
| Date Type: |
Completion |
| Defense Date: |
5 May 2006 |
| Approval Date: |
27 September 2006 |
| Submission Date: |
18 July 2006 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
MSBeng - Master of Science in Bioengineering |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cancer; cell migration; profilin |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07182006-015907/, etd-07182006-015907 |
| Date Deposited: |
10 Nov 2011 19:51 |
| Last Modified: |
19 Dec 2016 14:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8427 |
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