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Conditional Loss of the Mitotic Spindle Checkpoint in Chromosomal Instability and Tumorigenesis
The transformation of normal breast epithelium to invasive breast cancer is believed to require the activation of dominant oncogenes and loss of tumor suppressor genes. Genomic instability occurs in tumor cells and is widely believed to contribute to the initiation and progression to a fully malignant phenotype. Chromosomal instability results when chromosome mis-segregation occurs, creating aneuploid tumor cells. The mitotic spindle checkpoint helps prevent mis-segregation by blocking chromosome segregation until all chromosomes are properly aligned on the metaphase plate. Loss of the spindle checkpoint occurs in a majority of cancer cells. Mutations that result in a truncated Bub1 spindle checkpoint protein are found in a subset of human tumors. Naturally occurring Bub1 mutants when introduced into normal cells can impart a dominant loss of the spindle checkpoint. The goal of this project is to develop dominant negative alleles of Bub1 to conditionally and reversibly inhibit the mitotic spindle checkpoint in tissue culture and mouse model systems. We will test the hypothesis that loss of the spindle checkpoint can directly cooperate with oncogene signaling for malignant transformation of breast epithelium. Loss of the mitotic spindle checkpoint prevents mitotic arrest when cells are treated with microtubule inhibitors, such as taxanes. The effects of microtubule inhibitors in the presence of spindle checkpoint loss might be predicted to cause increased aneuploidy or, alternately, lead to increased cell death. The mouse model system developed in this project will allow direct analysis of the effects of taxane treatment on cells lacking the spindle checkpoint in vivo. Importantly, this model system should allow us to examine the effect of re-instating the mitotic spindle checkpoint in tumor cells. We will determine if spindle checkpoint loss is required for tumor maintenance.
Breast cancer results from the accumulation of damage to the genetic material of otherwise normal breast cells. The types of genetic alteration which result in invasive cancer can include mutations of known cancer causing genes, but also very frequently involves mutations which make the genetic material more “unstable”, allowing additional mutations to accumulate at a faster rate. One type of genomic instability that occurs frequently in tumor cells is due to the inability of dividing cells to equally and unerringly distribute their genetic material amongst the two daughter cells. This type of genomic instability, known as chromosomal instability, is the focus of this project. Currently, there is no direct way to test the effect of chromosome instability in normal breast cells. We propose to generate a new mouse strain in which we can precisely and reversibly cause chromosome instability in normal breast cells. We will test if causing chromosomal instability is sufficient to give rise to breast cancer, or if it will permit known cancer causing genes to more readily turn normal cells into cancer cells. Our approach will also have important implications for breast cancer treatment, since we can determine if turning off chromosomal instability in an established tumor will prevent its further growth or cause it to shrink.