Do Structural Missense Variants in the ATM Gene Found in Women With Breast Cancer Cause Breast Cancer in "Knock-in" Mouse Strains?
Annual rept. 1 Apr 2005-31 Mar 2006
CITY OF HOPE BECKMAN RESEARCH INST DUARTE CA
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The central hypothesis is that knock-in mice lines are made for two human cohort-specific missense mutations will develop breast cancer with dominant inheritance in a subset of animals. It also is hypothesized that other cancers will be more frequent as well. If correct it follows that the ATM gene is the first known example of a sup-oncogene i.e., a tumor suppressor gene for lymphoma Leukemia and an oncogene for breast cancer. More generally, it is hypothesized that an increased risk for breast cancer due to ATM mutations most commonly derives from cohort-specific missense mutation, that do not cause A-T in a homozygous state and occasionally from a subset of A-T carriers that have non-truncating mutations. Two in human cohort-specific missense variants from our previous case-control analysis will be generated in mice using mouse knock-in technology. The rate and time course of cancer incidence will be determined in these mice in comparison to wild type littermates and an A-T- causing non-truncating structural variant. Since the mouse Atm gene is extremely close to the human gene in structure and function, mouse models with only a single alteration in the gene can be used to assess the effects of this alteration on tumor formation, especially mammary tumors, in mice. If a variety of uncommon missense variants are shown to predispose to breast cancer, there are important diagnostic, preventive, and therapeutic I implications for women at risk for breast cancer.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research