The Role of Cdk4 in Her2 Driven Centrosome Amplification Pubblico
Pitner, Mary Kathryn Harrison (2013)
Abstract
Centrosome amplification (CA) is a contributor to carcinogenesis, generating aneuploidy and chromosome instability. Previous work shows that breast adenocarcinomas have a higher frequency of centrosome defects compared to normal breast tissues. Abnormal centrosome phenotypes are found in pre-malignant lesions, suggesting an early role in breast carcinogenesis. However, the role of CA in breast cancers remains elusive. The long-term goal of the work presented here is to assess the role of CA in mammary cancers by identifying how specific oncogenes signal CA. Identification of pathways and regulatory molecules involved in the generation of CA is essential to understanding its role in breast tumorigenesis. We established a breast cancer model of CA using Her2+ cells. Our goal was to identify centrosome cycle molecules that are deregulated by aberrant Her2 signaling and the mechanisms driving CA. Our results show some Her2+ breast cancer cell lines harbor both CA and binucleation. Abolishing the expression of Cdk4 abrogated both CA and binucleation in these cells. We also found the source of binucleation in these cells to be defective cytokinesis that is normalized by downregulation of Cdk4. Protein levels of Nek2 diminish upon Cdk4 knockdown, suggesting a molecular connection between Cdk4 and Nek2. Knockdown of Nek2 reduces CA and binucleation in this model while its overexpression further enhances CA. We conclude that CA is modulated through Cdk4 and Nek2 signaling, and that binucleation is a likely source of CA in Her2+ breast cancer cells.
Table of Contents
Chapter 1: Introduction...................................................................................................1
Figures..................................................................................................................24
Chapter 2: Cdk2 and Cdk4 regulate the centrosome cycle, and are critical mediators of
centrosome amplification in p53-null cells.......................................................................28
Figures..................................................................................................................64
Chapter 3: The Ras oncogene signals centrosome amplification in mammary epithelial cells
through cyclin D1/Cdk4 and Nek2...................................................................................80
Figures..................................................................................................................93
Chapter 4: Cdk4 and Nek2 signal binucleation and centrosome ampification in a Her2+
breast cancer model....................................................................................................103
Figures................................................................................................................125
Chapter 5: Discussion..................................................................................................140
Figures................................................................................................................150
References.................................................................................................................152
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