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-tomesenchymal 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.
Keywords: Aryl hydrocarbon receptor, ectopic overexpression, mammary epithelia, transformation, breast cancer, progression, basic helix-loop-helix, retinoblastoma, cyclin-dependent kinase, fluorescence activated cell sorter
Current Cancer Drug Targets
Title: Malignant Transformation of Mammary Epithelial Cells by Ectopic Overexpression of the Aryl Hydrocarbon Receptor
Volume: 11 Issue: 5
Author(s): J. Brooks and S. E. Eltom
Affiliation:
Keywords: Aryl hydrocarbon receptor, ectopic overexpression, mammary epithelia, transformation, breast cancer, progression, basic helix-loop-helix, retinoblastoma, cyclin-dependent kinase, fluorescence activated cell sorter
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-tomesenchymal 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.
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Cite this article as:
Brooks J. and E. Eltom S., Malignant Transformation of Mammary Epithelial Cells by Ectopic Overexpression of the Aryl Hydrocarbon Receptor, Current Cancer Drug Targets 2011; 11 (5) . https://dx.doi.org/10.2174/156800911795655967
DOI https://dx.doi.org/10.2174/156800911795655967 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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