title: Malignant transformation of mammary epithelial cells by ectopic overexpression of the aryl hydrocarbon receptor.
abstract: The aryl hydrocarbon receptor (AhR) is a ligand activated basic helix-loop-helix transcription factor that binds to environmental poly aromatic hydrocarbons (PAH) and mediates their toxic and carcinogenic responses. There is ample documentation for the role of AhR in PAH-induced carcinogenicity. However, in this report we addressed whether overexpression of AhR alone is sufficient to induce carcinogenic transformation in human mammary epithelial cells (HMEC). Retroviral expression vectors were used to develop a series of stable cell lines expressing varying levels of AhR protein in an immortalized normal HMEC with relatively low endogenous AhR expression. The resulting increase in AhR expression and activity correlated with the development of cellular malignant phenotypes, most significantly epithelial-to-mesenchymal transition. Clones overexpressing AhR by more than 3-fold, exhibited a 50% decrease in population doubling time. Cell cycle analysis revealed that this increase in proliferation rates was due to an enhanced cell cycle progression by increasing the percentage of cells transiting into S- and G2/M phases. Cells overexpressing AhR exhibited enhanced motility and migration. Importantly, these cells acquired the ability to invade matrigel matrix, where more than 80% of plated cells invaded the matrigel matrix within 24 h, whereas none of parental or the vector control HMEC were able to invade matrigel. Collectively, these data provide evidence for a direct role of AhR in the progression of breast carcinoma. The results suggest a novel therapeutic target that could be considered for treatment and prevention of breast cancer progression.
authors.affiliation: Graduate Program in Pharmacology, Department of Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brooks
authors.forename: S E
authors.initials: SE
authors.lastname: Eltom
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002999:Clone Cells; D003600:Cytosol / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human