Roles for the DNA Damage Checkpoint Protein HUS1 in Breast Cancer
Annual summary 1 Jul 2009-30 Jun 2010
CORNELL UNIV ITHACA NY
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Cancer is aberrant, uncontrolled cellular proliferation arising from an accumulation of mutations in growth regulatory genes. Two mammalian DNA damage checkpoint pathways, the Atm and Atr pathways, act to suppress tumor formation by preventing mutation accumulation and inducing senescence in response to oncogenic stimuli. Roles for the Atr pathway in tumor suppression are less understood, as deletion of any member of this pathway, including Hus1, results in embryonic lethality. To understand roles for Hus1 in breast cancer suppression, we developed mouse models featuring partial Hus1 impairment and are testing how Hus1 dysfunction affects cellular responses to activated oncogenes. Proliferation, immortalization, focus formation, soft agar, and transplantation assays suggest that cultured cells with reduced Hus1 levels are less able to be transformed. To elucidate roles for Hus1 as a tumor suppressor in vivo, mice expressing reduced levels of Hus1 were crossed to mice overexpressing ErbB2 in the mammary gland to generate a cohort of mice. Our preliminary results indicate that reduced Hus1 levels may decrease the capacity of cells to undergo transformation, suggesting that Hus1, or the Atr pathway, may be a possible target for breast cancer treatment.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research