Susan E. Andrew

My long-standing research interest is in instability of the mammalian genome and its relevance to human disease. The purpose and long term objective of my research is to further understand the consequences of mammalian genomic DNA instability. One goal is to determine the relation between mutation frequency and tumourigenesis in the absence of DNA mismatch repair and identify genes in the multi-step pathway of tumourigenesis. Individuals deficient in DNA mismatch repair develop the cancer syndrome Lynch syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer. We have several projects underway investigating the role of DNA mismatch repair in different cancer types, including skin cancer and haematological malignancy.

We are also particularly interested in the role DNA mismatch repair may play in signaling DNA damage to other cellular proteins involved in initiating apoptotic pathways. Recent evidence suggests a novel and exciting new role for the mismatch repair proteins in initiating cell cycle arrest and apoptosis after exposure to DNA damaging agents. We collaborate closely with Dr. Victor at Queen’s University. Together, we have demonstrated that apoptosis is reduced after UVB damage in the absence of mismatch repair and this is associated with an earlier onset of skin cancer in mice lacking mismatch repair. Understanding the mechanism by which lack of mismatch repair provides resistance to UVB by reducing the ability of the cell to induce apoptosis is important for understanding skin tumor pathways. We also are investigating new treatments for malignant melanoma by using molecular methods to make melanoma cells more sensitive to apoptosis.

Finally, the current understanding of the sensors for DNA damage and initiation of apoptosis is weak. The role of the DNA mismatch repair proteins as sensors of DNA damage caused by a variety of damaging agents and influencing signaling pathways regulating initiation of apoptosis is novel. We collaborate with Dr. Raymond Lai, Laboratory Medicine and Pathology to investigate novel interactions of the mismatch repair proteins with oncogenic proteins such as NPM-ALK, and elucidating the effects on protein signaling that can contribute to carcinogenesis.

Keuling AM, Felton KE, Parker AA, Akbari M, Andrew SE, Tron VA.RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway. PLoS One. 2009 Aug 17;4(8):e6651.

Tron VA.Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancer.Br J Dermatol. 2008 Jan;158(1):59-69. Epub 2007 Oct 26.

Young LC, Keuling AM, Lai R, Nation PN, Tron VA, Andrew SE.The associated contributions of p53 and the DNA mismatch repair protein Msh6 to spontaneous tumorigenesis. Carcinogenesis. 2007 Oct;28(10):2131-8. Epub 2007 Jul 5.

Narine KA, Felton KE, Parker AA, Tron VA, Andrew SE. Non-tumor cells from an MSH2-null individual show altered cell cycle effects post-UVB. Oncol Rep. 2007 Dec;18(6):1403-11.

Felton KE, Gilchrist DM, Andrew SE.Constitutive deficiency in DNA mismatch repair. Clin Genet. 2007 Jun;71(6):483-98. Review.

Campbell MR, Wang Y, Andrew SE, Liu Y. Msh2 deficiency leads to chromsomal abnormalitites centrosome amplification, and telomere capping defect. Oncogene. 25(17):2531-6 (2006)

Campbell, MR, Nation N, Andrew SE. A lack of DNA mismatch repair on an athymic murine background predisposes to hematoglogic malignancy. Cancer Res. 65:2626-35 (2005)

Young LC, Thulien KJ, Campbell MR, Tron VA, Andrew SE. DNA mismatch repair proteins promote apoptosis and suppress tumorigenesis in response to UVB irradiation: and in vivo study. Carcinogenesis. 2004 25:1281-1287.

Peters AC, Young LC, Maeda T, Tron VA, Andrew SE. Mammalian DNA mismatch repair protects cells from UVB-induced DNA damage by facilitating apoptosis and p53 activation. DNA Repair (Amst). 2003 Apr 2;2(4):427-35.

Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ, Andrew SE. A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res, Jan 15;62(2):359-62 (2002).