Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer

Abstract

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 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>5≫2, 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.

Differential Effect of ITE on the Aryl Hydrocarbon Receptor Signaling in Breast Cancer Tissue: A Histopathological Study

“…In addition to human breast cancer, increased expression of AhR has also been found in human lung cancer, liver cancer, and prostate cancer (Deuster et al, 2019;Baker et al, 2020). Similar to other study, as the AhR staining is almost negative inside the normal breast tissue; relatively high levels of AhR expression inside the breast cancer could be used as potential marker for breast cancers (Spink et al, 2015). Additionally, AhR gene polymorphisms was reported to be closely related to the increased risk of lung and breast cancers (Aftabi et al, 2016;Vacher et al, 2018), further study regarding this expression pattern of breast cancer is needed to confirm the observations.…”

Structure-Activity Relationships of the Main Bioactive Constituents of Euodia rutaecarpa on Aryl Hydrocarbon Receptor Activation and Associated Bile Acid Homeostasis

“…AHR is highly inducible by a wide range of exogenous compounds (Fernandez-Salguero et al, 1996;Schmidt et al, 1996;Spink et al, 2015), and its activation could either cause metabolic activation of chemical toxicants and procarcinogens or inactivate xenobiotics (Shimizu et al, 2000;Connor et al, 2008;de Waard et al, 2008;Veldhoen et al, 2009). The biologic effects of various AHR activators vary, thus highlighting the need for determining the structure-activity relationship for AHR and its ligands (Connor et al, 2008;de Waard et al, 2008;Veldhoen et al, 2009).…”

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

“…In some studies, the AhR acts as a potent tumor suppressor, recently being shown to repress melanoma growth55, liver carcinogenesis56 and inflammation-associated colorectal tumorigenesis57. Genetic variations in AHR are also implicated in lung cancer susceptibility amongst smokers, where such variation may affect AhR protein expression and/or activity585960. miR-96 is also significantly increased in lung cancer50, lending to the possibility that low AhR (due to genetic alteration) could enhance lung cancer susceptibility in smokers through increased expression of miR-96.…”