Chromosomal instability in cancer pathogenesis and treatment

When cells divide, their DNA is packaged into parcels called chromosomes. Chromosomes in cells from human cancers of the breast, ovary, prostate or colon are often abnormal in their structure or number. We have been studying a gene (called BRCA2), which is inactivated in women from families in which there is a high risk of cancers of the breast or ovary. We have recently found that BRCA2 plays a direct role in preserving the structure and number of chromosomes when cells divide, and that its inactivation can trigger the formation of cancer cells. In this work, we propose to study how BRCA2 and related genes protect chromosomes, using genetic studies on cells we can grow in the laboratory. The information we gain from these studies will be used to predict and test the steps taken by normal breast or ovary cells in women who inherit abnormal BRCA2 to become cancer cells. We expect this work will lead to a better understanding of how cancer develops in people who inherit such defective genes. We also expect in the future that it will help us to predict which anti-cancer treatments can be most effectively used in these conditions.

Instability of chromosome structure and number frequently occurs in cells from human cancers. The relationship between chromosomal instability and cancer pathogenesis ? very probably causal ? is poorly understood. How chromosomal instability affects the response of cancer cells to radiation and chemotherapeutic agents is unclear. We aim (A) to understand how inactivation of the BRCA2 breast cancer susceptibility protein or related molecules causes instability of chromosome structure and number, (B) to identify the molecular events that lead to the transformation of chromosomally unstable cells, and (C) to elucidate how chromosomal instability affects the response of cancer cells to anti-cancer therapies.