Our overall goal is to determine the role of the adenomatous polyposis coli (APC) gene in DNA damage-induced DNA repair activity and breast carcinogenesis. Down-regulation of APC is a predominant phenomenon in breast cancer, but neither its role in this disease nor the molecular alteration(s) underlying carcinogenesis in normal breast epithelial cells have been characterized. In the past, the role of mutated APC has been investigated in various cancers. In our studies, we propose a highly novel concept that it is the decreased level of APC that is responsible for the decreased DNA repair capacity, which is the cellular mechanisms underlying carcinogenesis in normal breast epithelial cells. Our preliminary data indicate that APC protein interacts with base excision repair proteins, including proliferating cell nuclear antigen (PCNA) and apurinic/apydmidinic endonudease (APE). We hypothesize that the normal levels of APC promote formation of an active complex with PCNA and APE that facilitates repair of abasic DNA through a base excision repair pathway thereby preventing accumulation of gene mutations in normal breast epithelial cells. Decreased levels of APC result in inappropriate binding of the PCNA/APE-complex at the abasic DNA, decreased base excision repair activity, accumulation of gene mutations, and transformation of normal breast epithelial cells. To test this hypothesis, we will use human normal breast epithelial cell lines treated with DNA-damaging mammary carcinogens. We will: (1) Determine that the carcinogen exposure attenuates APC gene expression in normal breast epithelial ceils; (2) Characterize the structure-function relationships of APC with PCNA and APE; (3) Utilize a novel base excision repair assay system with functional purified repair complexes to characterize changes in the dynamics of these complexes in carcinogen-treated normal breast epithelial cell lines; and (4) Examine the function of APC as a PCNA recruiting factor onto abasic DNA to regulate base excision repair activity in carcinogen-treated and untreated normal breast epithelial cells. This project will, for the first time, provide a novel paradigm for understanding the molecular basis for APC function in DNA damage-induced base excision repair and the transformation of normal breast epithelial cells and will facilitate development of chemotherapeutics for prevention of breast cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100247-05
Application #
7234812
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
2003-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$276,266
Indirect Cost
Name
University of Florida
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Narayan, Satya; Jaiswal, Aruna S; Law, Brian K et al. (2016) Interaction between APC and Fen1 during breast carcinogenesis. DNA Repair (Amst) 41:54-62
Narayan, Satya; Sharma, Ritika (2015) Molecular mechanism of adenomatous polyposis coli-induced blockade of base excision repair pathway in colorectal carcinogenesis. Life Sci 139:145-52
Jaiswal, Aruna S; Hirsch-Weil, Dimitri; Proulx, Erick R et al. (2014) Anti-tumor activity of novel biisoquinoline derivatives against breast cancers. Bioorg Med Chem Lett 24:4850-3
Jaiswal, Aruna S; Armas, Melissa L; Izumi, Tadahide et al. (2012) Adenomatous polyposis coli interacts with flap endonuclease 1 to block its nuclear entry and function. Neoplasia 14:495-508
Jaiswal, Aruna S; Banerjee, Sanjeev; Aneja, Ritu et al. (2011) DNA polymerase ? as a novel target for chemotherapeutic intervention of colorectal cancer. PLoS One 6:e16691
Jaiswal, Aruna S; Narayan, Satya (2011) Assembly of the base excision repair complex on abasic DNA and role of adenomatous polyposis coli on its functional activity. Biochemistry 50:1901-9
Jaiswal, Aruna S; Banerjee, Sanjeev; Panda, Harekrushna et al. (2009) A novel inhibitor of DNA polymerase beta enhances the ability of temozolomide to impair the growth of colon cancer cells. Mol Cancer Res 7:1973-83
Panda, Harekrushna; Jaiswal, Aruna S; Corsino, Patrick E et al. (2009) Amino acid Asp181 of 5'-flap endonuclease 1 is a useful target for chemotherapeutic development. Biochemistry 48:9952-8
Connors, S K; Balusu, R; Kundu, C N et al. (2009) C/EBPbeta-mediated transcriptional regulation of bcl-xl gene expression in human breast epithelial cells in response to cigarette smoke condensate. Oncogene 28:921-32
Jaiswal, Aruna S; Aneja, Ritu; Connors, Shahnjayla K et al. (2009) 9-bromonoscapine-induced mitotic arrest of cigarette smoke condensate-transformed breast epithelial cells. J Cell Biochem 106:1146-56

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