A Role for the AHR, an Environmental Pollutant Activated Receptor and Transcription Factor, in Mammary Tumor Progression
S Narasimhan, DH Sherr. Boston University School of Medicine, Boston, MA; Boston University School of Public Health, Boston, MA
Background: Polycyclic aromatic hydrocarbons (PAH) and polychlorinated biphenyls (PCBs) likely play a role in human cancer initiation through activation of the AhR (aryl hydrocarbon receptor/transcription factor) and AhR-dependent induction of cytochrome P450 enzymes (CYP1A1 and CYP1B1). These enzymes metabolize at least some AhR ligands into carcinogenic intermediates, resulting in the genetic mutations that are the hallmark of cancer.Previous studies in our laboratory using murine and rat models of mammary tumorigenesis demonstrate nuclear AhR expression in primary mammary tumors, a result consistent with constitutive AhR transcriptional activity and suggestive of ongoing epigenetic AhR signaling.
Design: Here, we postulate that constitutively active AhR plays a role in regulating genes involved in tumor progression through epigenetic signaling, even in the absence of environmental ligands. To test this hypothesis, AhR activity in two human mammary tumor cell lines, Hs578T and BP1, was down-regulated by transient transfection or stable transduction of an AhR repressor (AhRR) or AhR siRNA, and the ability of these cells to exhibit an invasive phenotype were evaluated. Hs578T is a human malignant mammary carcinosarcoma and BP1 is a PAH-induced malignant mammary epithelial cell line, both of which exhibit invasive phenotypes in vitro and metastasis in vivo.
Results: AhR down-regulation in either line altered colony morphology in 3D cultures and significantly reduced tumor cell invasiveness in modified Boyden chambers were observed. Analyses of RNA arrays further suggested that the AhR contributes to tumor progression through transcriptional regulation of master gene regulators of tumor invasion.
Conclusions: These data agree with the hypothesis that constitutively active AhR promotes tumor invasion and that environmental AhR ligands may either enhance or alter this capability. Furthermore, they provide a specific molecular mechanism through which common environmental chemicals, exposure to which is associated with breast cancer incidence, may contribute to metastatic progression, the underlying cause of breast cancer deaths. Finally, these studies provide facile models with which to screen naturally occurring AhR inhibitors (e.g., bioflavonoids and polyphenols) as potential breast cancer preventatives or therapeutics.
Monday, March 9, 2009 1:00 PM
Poster Session II # 56, Monday Afternoon