TY - JOUR
T1 - Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer
AU - Spink, Barbara C.
AU - Bloom, Michael S.
AU - Wu, Susan
AU - Sell, Stewart
AU - Schneider, Erasmus
AU - Ding, Xinxin
AU - Spink, David C.
N1 - Funding Information:
This work was supported by the National Institutes of Health grants CA081243 and CA170960 (to DCS), grant CA092596 (to XD), and a grant from the New York State Attorney General's office (to ES) ( N1407157 ). The authors gratefully acknowledge use of the Wadsworth Center's Media and Tissue Culture Facility, the Biochemistry, Histopathology, and Applied Genomic Technologies Core Facilities, and the Molecular Diagnostics Laboratory. We thank Richard Cole, Director of the Wadsworth Center's Advanced Light Microscopy Core Facility, for helpful advice on fixation of frozen tissue. The AHR promoter plasmid, pGL3-hAhRP, was a generous gift from Drs. Sandra Wolff and Josef Abel of the IUF-Leibniz Research Institute for Environmental Medicine, Heinrich-Heine-University, Düsseldorf, Germany. DNA from 3 species of macaque was a generous gift of Dr. Roger Wiseman of the Genetics Services Unit of the Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI. DNA from gorilla was a generous gift of Dr. Michael I. Jensen-Seaman, Department of Biological Sciences, Duquesne University, Pittsburgh, PA. DNA from chimpanzee was provided by Dr. Jerilyn Pecotte of the Southwest National Primate Research Center, San Antonio, TX (Biomaterials Distribution Program), which was funded by the National Center for Research Resources ( P51 RR013986 ) and is currently supported by the Office of Research Infrastructure Programs / OD P51 OD011133 . Conflict of interest statement The authors have nothing to disclose.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC)n, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC)2 alleles were observed; however, in western gorilla, (GGGGC)n alleles with n=2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC)n was n=4>5c2, 6. When frequencies of the (GGGGC)n alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC)2 was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC)n short tandem repeats are inherited, and that the (GGGGC)2 allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility.
AB - The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC)n, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC)2 alleles were observed; however, in western gorilla, (GGGGC)n alleles with n=2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC)n was n=4>5c2, 6. When frequencies of the (GGGGC)n alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC)2 was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC)n short tandem repeats are inherited, and that the (GGGGC)2 allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility.
KW - (GGGGC) repeat polymorphism
KW - Aryl hydrocarbon receptor
KW - Breast cancer
KW - Colon cancer
KW - Lung cancer
KW - Short tandem repeat
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U2 - 10.1016/j.taap.2014.10.017
DO - 10.1016/j.taap.2014.10.017
M3 - Article
C2 - 25447411
AN - SCOPUS:84912035647
VL - 282
SP - 30
EP - 41
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 1
ER -