DNA repair proteins affect the response of cells to genotoxic stresses, and are often mutated or silenced in cancers. The RecQ helicases are a family of DNA repair proteins whose inactivation can predispose individuals to cancer (e.g. Werner syndrome, etc.) and can enhance the anti-tumor effects of chemotherapy. The biological significance of inactivation of the RecQ helicases in cancer is largely unknown, although predicted to be of importance based on studies of WRN and BlM in colorectal and breast cancer. Thus, we will assess the expression of the RecQ helicases, BlM, WRN, RECQL, RECQL4, and RECQL5 as well as candidate RECQ helicase interacting proteins in colorectal and breast cancer, and will determine how these proteins affect the responsiveness of these cancers to chemotherapeutic agents, especially TOPO1 inhibitors. Furthermore, WRN and likely the other RecQ helicases can be inactivated in cancer by an epigenetic mechanism-aberrant DNA methylation. Thus, the role of DNA methylation in silencing the RecQ helicases will be assessed and correlated with the clinical behavior of these cancers.
The Specific Aims of these studies are:
Aim 1 : To determine the frequency of loss of expression and epigenetic inactivation of RecQ helicases in common epithelial cancers: colorectal cancer and breast cancer.
Aim 2 : To determine the role of WRN, BlM, and RECQL4 inactivation and RECQ helicase interacting proteins in modifying the effect of chemotherapy on colorectal cancers (CRC).
Aim3 : To determine the role of WRN, BlM, and RECQL4 inactivation and RECQ helicase interacting proteins in modulating the effect of chemotherapy on breast cancers (BrCA).
In Aims 2 and 3, The RECQ helicase interacting proteins to be studied will be selected from candidates that are genetically or epigenetically altered in CRC or BrCA (e.g. MRE11 and MlH1) and aberrantly expressed. We will determine if methylation or loss of expression of the RECQ helicases and/or intereacting proteins affects sensitivity to chemotherapy by correlating the methylation and expression status of these genes in to response to treatment using two well annotated cohorts from clinical trials (CALBGB 89803 and SWOG S9313). These studies will be done with the support of Core A and Core C as well as Projects 2 and 3.
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