Aneuploidy, an abnormal chromosome number, is a common characteristic of tumor cells, occurring in ~85% of all human cancers. Aneuploidy frequently arises due to errors in chromosome segregation during mitosis. The high prevalence of aneuploidy and mitotic errors in tumor cells prompted the hypothesis that aneuploidy is a cause of tumor genesis. However, this has been difficult to establish. We recently discovered that aneuploidy caused by reduction of the mitosis-specific kinesin-like motor protein CENP- E (CENtromere associated Protein-E) both promotes and suppresses tumors, depending on the context. These findings may have therapeutic implications, particularly since an inhibitor of CENP-E motor activity is currently in clinical trials. The overall goal of this proposal is to define the context-dependent factors that determine whether aneuploidy caused by reduction of CENP-E will promote or suppress tumors. Preliminary studies suggest that tumors with a pre-existing level of genetic instability are susceptible to aneuploidy-mediated tumor suppression, which occurs due to an increase in cell death caused by loss of both copies of one or more essential chromosomes. Experiments in Aim 1 will determine the mechanism(s) of aneuploidy-mediated cell death, and provide a basis to predict which tumors are susceptible.
Aim 2 will determine whether tumors induced by reduction or mutation of the tumor suppressors p53 and APC (Adenomatous Polyposis Coli) are susceptible to aneuploidy-mediated cell death caused by reduction of CENP-E. Previous studies have shown that reduction of CENP-E suppresses tumors in animals lacking the p19ARF tumor suppressor.
Aim 3 will extend preliminary studies that identified a previously unsuspected role for p19ARF in chromosome segregation during mitosis. Together, these experiments will define the characteristics that determine whether a given tumor is susceptible to aneuploidy-mediated tumor suppression and will provide translationally relevant information for use of the CENP-E inhibitor currently in clinical trials.
Cancer is the second most common cause of death in the USA. Errors during cell division are common in cancer cells, but the effects of these errors on tumors are complex. The experiments in this proposal will define how errors during cell division affect tumors, with the ultimate goal of producing clinically useful therapies.
|Burkard, Mark E; Weaver, Beth A (2017) Tuning Chromosomal Instability to Optimize Tumor Fitness. Cancer Discov 7:134-136|
|Funk, Laura C; Zasadil, Lauren M; Weaver, Beth A (2016) Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression. Dev Cell 39:638-652|
|Cunningham, Chelsea E; Li, Shuangshuang; Vizeacoumar, Frederick S et al. (2016) Therapeutic relevance of the protein phosphatase 2A in cancer. Oncotarget 7:61544-61561|
|Denu, Ryan A; Zasadil, Lauren M; Kanugh, Craig et al. (2016) Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer. BMC Cancer 16:47|
|Zasadil, Lauren M; Britigan, Eric M C; Ryan, Sean D et al. (2016) High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation. Mol Biol Cell 27:1981-9|
|Hwang, Byounghoon; McCool, Kevin; Wan, Jun et al. (2015) IPO3-mediated Nonclassical Nuclear Import of NF-?B Essential Modulator (NEMO) Drives DNA Damage-dependent NF-?B Activation. J Biol Chem 290:17967-84|
|Wan, Jun; Zhu, Fen; Zasadil, Lauren M et al. (2014) A Golgi-localized pool of the mitotic checkpoint component Mad1 controls integrin secretion and cell migration. Curr Biol 24:2687-92|
|Britigan, Eric M C; Wan, Jun; Zasadil, Lauren M et al. (2014) The ARF tumor suppressor prevents chromosomal instability and ensures mitotic checkpoint fidelity through regulation of Aurora B. Mol Biol Cell 25:2761-73|
|Zasadil, Lauren M; Andersen, Kristen A; Yeum, Dabin et al. (2014) Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med 6:229ra43|
|Weaver, Beth A (2014) How Taxol/paclitaxel kills cancer cells. Mol Biol Cell 25:2677-81|
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