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Aryl hydrocarbon receptor regulation of canine ErbB4

Grant number: 19/26266-3
Support type:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): March 25, 2020
Effective date (End): June 24, 2020
Field of knowledge:Agronomical Sciences - Veterinary Medicine - Animal Pathology
Principal Investigator:Renee Laufer Amorim
Grantee:Antonio Fernando Leis Filho
Supervisor abroad: Robert B. Rebhun
Home Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Local de pesquisa : University of California, Davis (UC Davis), United States  
Associated to the scholarship:18/14041-4 - Lapatinib effects on Her2+ and Her2- canine mammary carcinoma cells cultured in vitro, BP.MS

Abstract

The aryl hydrocarbon receptor (AHR) is a protein that can bind to specific DNA sequences located upstream of the target gene, regulating its transcription. These sequences are known as dioxin response elements (DREs) and are found throughout the genome of many species, potentially influencing thousands of genes producing a variety of beneficial or toxic biological effects, including cancer. Dioxin is among a group of compounds that act as ligands for AHR, which includes other synthetic as well as naturally occurring ones. Importantly, AHR binding can act as either an enhancer or a suppressor of transcription, so the toxic or beneficial effect of these chemicals is not necessarily caused by AHR, therefore, the ligands themselves can have dramatically different biological effects acting as toxins or promoting health benefits. Using whole genome sequencing data an indel located upstream of the canine ERBB4 transcription start site (TSS) that matches the DRE sequence was identified. The purpose of this proposal is to investigate one possible way in which AHR may influence cancer risk and age of development. This short DRE sequence is often missing in golden retrievers that develop cancer at young ages, compared to dogs that live longer or develop cancer at older ages. These findings suggest that AHR may play a role in ERBB4 regulation and that such regulation may also be important for cancer prevention and longevity. This proposal aims to investigate that hypothesis and evaluate the role of AHR on ERBB4 expression in dogs. Results from this study may identify a novel mechanism of ERBB4 regulation and warrant future investigations into the role of AHR and ERBB4 in cancer susceptibility. (AU)