title: Insulin like growth factor 2 regulation of aryl hydrocarbon receptor in MCF-7 breast cancer cells.
abstract: Insulin like growth factor (IGF)-1 and IGF-2 stimulate normal growth, development and breast cancer cell proliferation. Cyclin D1 (CCND1) promotes cell cycle by inhibiting retinoblastoma protein (RB1). The aryl hydrocarbon receptor (AHR) is a major xenobiotic receptor that also regulates cell cycle. The purpose of this study was to investigate whether IGF-2 promotes MCF-7 breast cancer proliferation by inducing AHR. Western blot and quantitative real time PCR (Q-PCR) analysis revealed that IGF-2 induced an approximately 2-fold increase (P<.001) in the expression of AHR and CCND1. Chromatin immunoprecipitation (ChIP), followed by Q-PCR indicated that IGF-2 promoted (P<.001) a 7-fold increase in AHR binding on the CCND1 promoter. AHR knockdown significantly (P<.001) inhibited IGF-2 stimulated increases in CCND1 mRNA and protein. AHR knockdown cells were less (P<.001) responsive to the proliferative effects of IGF-2 than control cells. Collectively, our findings have revealed a new regulatory mechanism by which IGF-2 induction of AHR promotes the expression of CCND1 and the proliferation of MCF-7 cells. This previously uncharacterized pathway could be important for the proliferation of IGF responsive cancer cells that also express AHR.
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Tomblin
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: salisburyt@marshall.edu.
authors.forename: Travis B
authors.initials: TB
authors.lastname: Salisbury
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism* / Q000494:pharmacology; D061986:MCF-7 Cells; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D019363:Cytochrome P-450 CYP1A1; D007335:Insulin-Like Growth Factor II; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C530104:CCND1 protein, human; C035170:IGF2 protein, human
keywords: Aryl hydrocarbon receptor; Breast cancer cells; CCND1; IGF-2