Summary
Work in the Lingle laboratory has focused on the role of centrosome amplification in the development of cancer. In 1998, we published the first documentation of centrosome amplification in human tumors and have since demonstrated that an excess of pericentriolar material is associated with high frequencies of abnormal mitoses in breast cancers. Furthermore, the extent of centrosome amplification has a significant linear correlation with chromosomal instability in human breast cancer. We also learned that centrosomes in breast cancers with mutations in p53 have significantly greater microtubule nucleation activity than those in cancers with wild type p53. This is the first demonstration that p53 can affect the cytoskeleton. Much of this work has been done in collaboration with the Salisbury laboratory, with assistance from the Vile laboratory, and with support from the Women's Cancer and the Cell Biology Programs of the Mayo Clinic Cancer Center. Research has been funded by the Department of Defense Breast Cancer Research Program, the Breast Cancer Research Foundation, the Mayo Clinic Cancer Center, and the Mayo Foundation.
Specific Research Topics:
Differential effects of specific p53 mutations on the cytoskeleton - Work in progress indicates that specific p53 mutations may have different effects on the microtubule cytoskeleton. These studies, which use adenoviral vectors to deliver mutant p53 to normal human mammary epithelial cells in culture, monitor centrosome function and microtubule growth properties in cells expressing different p53 mutants. Information gained from this approach may prove to be useful in making treatment decisions regarding the use of microtubule poisons as chemotherapies for patients with known p53 mutations.
Identification of genes whose expression correlates with centrosome size in cancer.
Our recent finding that the degree of centrosome amplification correlates linearly with chromosomal instability in breast cancer has prompted studies designed to correlate gene expression with the degree of centrosome amplification. This approach yielded 36 genes whose expression increases with increased centrosome size. Included are 7 genes known or suspected to increase tumor growth along with 18 novel genes that therefore are "guilty by association" of being involved in increased tumor growth. These 18 novel genes are candidates for investigation as possible tumor promoters.
Analysis of expression of centrosome-associated genes in breast cancer.
Analysis of 165 genes associated with centrosome structure and function and with the mitotic apparatus identified more than 50 genes with expression patterns that differentiate between normal and cancer tissues. Eight of these genes are expressed at the highest levels in the most advanced or aggressive cancers. We are in the process of confirming these patterns in a larger cohort of samples. The possible effects of under- and over-expression of these genes on chromosomal instability and cell transformation will be investigated in cell culture systems.