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Molecular Mechanisms Underlying Profilin-1’s Regulation of Tumorigenic Potential of Breast Cancer Cells

Jiang, Chang (2016) Molecular Mechanisms Underlying Profilin-1’s Regulation of Tumorigenic Potential of Breast Cancer Cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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A hallmark of oncogenic transformation is disruption of the actin cytoskeleton, which is partly attributed to altered expression and/or activity of proteins that bind to and regulate the state of polymerization of actin in cells. Profilin-1 (Pfn1) is a key regulator of actin polymerization that is downregulated in human breast cancer. Previous studies have also shown Pfn1 has a tumor-suppressive effect on triple-negative breast cancer (TNBC) cells with mesenchymal features, and Pfn1-induced growth suppression of TNBC cells is partly mediated by upregulation of cell-cycle inhibitor p27kip1 (p27). The aim of the first part of this dissertation was to elucidate the molecular mechanism of how Pfn1 elevation causes p27 accumulation in TNBC cells. It is demonstrated that Pfn1 overexpression leads to accumulation of p27 through promoting activation of AMP-activated kinase (AMPK) and AMPK-dependent phosphorylation of p27 on T198 residue (a post-translational modification that leads to increased protein stabilization of p27) secondary to a cadherin-mediated epithelial morphological reversion. These findings not only elucidate a potential mechanism of how Pfn1 may inhibit proliferation of mesenchymal TNBC cells, but also highlight a novel pathway of cadherin-mediated p27 induction and therefore cell-cycle control in cells. The aim of the second part of this dissertation was to investigate whether Pfn1 is a classic tumor-suppressive protein. Matrigel-based 3D-outgrowth assays that measure tumor-initiating capacity of breast cancer cells demonstrated that either depletion or elevation of Pfn1 expression impairs formation of filopodia-like structures (a feature that determines dormant vs proliferative phenotype) and outgrowth of TNBC cells suggesting that a balanced Pfn1 expression is most conducive for tumor-initiating capacity of TNBC cells. Furthermore, perturbing Pfn1 expression affects expression of stem cell-associated genes thereby impacting the overall stem-like phenotype of TNBC cells. Finally, the outgrowth-deficient phenotype of TNBC upon Pfn1-depletion can be rescued by modulating ECM component which suggests that alteration in cell-matrix adhesion and downstream signaling underlies the growth-related phenotypic changes induced by loss of Pfn1. Based on these results, we conclude that Pfn1 expression level is an important determinant for stemness and outgrowth potential of TNBC cells.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoy, Parthapar19@pitt.eduPAR19
Committee MemberDavidson, Lance Alad43@pitt.eduLAD43
Committee MemberShroff, Sanjeev G.sshroff@pitt.eduSSHROFF
Committee MemberSingh, Shivendra Vsinghs@upmc.eduSVS2
Date: 25 January 2016
Date Type: Publication
Defense Date: 30 June 2015
Approval Date: 25 January 2016
Submission Date: 16 November 2015
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 101
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: Profilin-1; p27kip1; AMPK; breast cancer; tumorigenesis; filopodia
Date Deposited: 25 Jan 2016 18:22
Last Modified: 25 Jan 2018 06:15


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