DNA DOUBLE STRAND REPAIR PROTEINS AND CANCER DIAGNOSIS

基因组不稳定性是癌细胞的标志，可由细胞毒性药物和电离辐射产生，并且发生有多种原因，包括细胞周期检查点控制的丧失或DNA损伤修复机制的缺陷。缺乏基因组完整性的维持提供了肿瘤进展和肿瘤异质性的机制。涉及修复DNA损伤和预防由于染色体片段化、易位或缺失导致的癌症形成的主要过程是双链断裂（DSB）修复途径。我们认为，参与DSB的肿瘤抑制基因和直接参与DNA双链断裂修复的基因表达的改变可能提供如何治疗特定癌症的信息。我们假设参与双链断裂修复的蛋白质的表达水平和/或细胞定位是临床上重要的生物学特征，其导致对细胞毒性化疗的治疗反应改善，并且在乳腺癌和其他癌症中具有更好的结果。 为了测试这一点，我们将生产生化试剂，使我们和其他研究人员能够确定DSB中涉及的特定蛋白质的表达或产生是否被癌细胞中的化疗药物改变。 这些信息将有助于确定独特的预后和预测指标，并帮助临床医生决定给定的患者是否应该接受特定的化疗。拟议的商业应用：针对这些参与DNA修复的蛋白质的抗体将有助于解剖和理解参与细胞对DNA损伤反应的途径。我们可以预期，这些蛋白质中的一种或多种可能在特定的癌症中是重要的，包括前列腺癌、结肠癌和乳腺癌，由此产生的抗体将是未来诊断这些疾病的有用工具。

Genomic instability, a hallmark of cancer cells, cart be produced by cytotoxic drugs and ionizing radiation.and occurs for multiple reasons, including loss of cell cycle checkpoint control or defects in the DNA damage repair machinery. The lack of maintenance of genomic integrity provides a mechanism for both tumor progression and tumor heterogeneity. A major process involved in repairing DNA damage and preventing cancer formation due to chromosomal fragmentation, translocations or deletions is the double strand break (DSB) repair pathway. We believe that the alteration in expression of tumor suppressor genes involved in DSB and genes directly involved with DNA double strand break repair may provide information on how to treat a particular cancer. We hypothesize that the expression levels and/or cellular localization of proteins involved in double strand break repair are clinically important biological features that lead to improved treatment response to cytotoxic chemotherapy and better outcome in breast and other cancers. To test this, we will generate the biochemical reagents to enable us and other researchers to determine if the expression or production of specific proteins involved in DSB are altered by chemotherapeutic drugs in cancer cells. This information will facilitate the determination of unique prognostic and predictive indicators and help clinicians decide whether a given patient should receive a specific chemotherapy. PROPOSED COMMERCIAL APPLICATIONS: Antibodies against these proteins involved in DNA repair will be useful in dissecting and understanding the pathways involved in the cellular response to DNA damage. We can anticipate that one or more of these proteins may be important in specific cancers, including prostrate, colon and breast cancer and the resulting antibodies will be useful tools in the future diagnosis of these diseases.