The Role of Chk1 in Breast Epithelial Cell Checkpoint Function
Abstract
The genetic evolution of normal breast epithelial cells into cancer cells is largely determined by the fidelity of DNA replication, repair, and cell cycle division. The control mechanisms that restrain cell cycle transition after DNA damage are known as cell cycle checkpoints. Loss or attenuation of checkpoint function can result in gene mutations, chromosome damage, and aneuploidy, all of which can contribute to breast tumorigeneiss. This proposal focuses on the 02 cell cycle checkpoint signaling pathway in breast epithelial cells and how one component of this checkpoint pathway, the Chkl kinase, may offer the potential for therapeutic intervention. The objective of the proposal is to test the following two-part hypothesis. First, Chkl kinase is activated by genotoxic stress and its activity is required for G2 checkpoint function in breast epithelial cells. Second, ablation of Chkl function in mammary epithelial cells will ablate G2 checkpoint function and sensitize cells to anticancer agents that induce DNA damage. The following specific aims are proposed to test this hypothesis: (1) To determine how Chkl is regulated after exposure of human breast epithelial cells to anticancer agents. (2) To determine if conditional knock-out of Chk 1 in mouse mammary epithelial cells abrogates G2 checkpoint function and sensitizes mammary epithelial cells to currently used anticancer agents.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2002
- Accession Number
- ADA410363
Entities
People
- Jennifer A. Pietenpol
Organizations
- Vanderbilt University Medical Center