TY - JOUR
T1 - Induction of the transferrin receptor gene by benzo[a]pyrene in breast cancer MCF-7 cells
T2 - Potential as a biomarker of PAH exposure
AU - Kemp, Michael Q.
AU - Liu, Wenjing
AU - Thorne, Patricia A.
AU - Kane, Michael D.
AU - Selmin, Ornella
AU - Romagnolo, Donate F.
PY - 2006/8
Y1 - 2006/8
N2 - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental DNA-damaging agents regarded as risk factors for human disease, including lung and breast cancer. The biotransformation of PAHs to carcinogenic metabolites is mediated by the aromatic hydrocarbon receptor (AhR), which activates transcription at xenobiotic responsive elements (XREs = 5′-GCGTG-3′) found in the promoter regions of genes encoding for detoxifying enzymes, including CYP1A1 and CYP1B1. In this study, we wished to identify novel biomarkers that may be useful in monitoring critical carcinogenic events of the breast induced by PAHs. Using a GeneMAP™ CancerArray, we analyzed in breast cancer MCF-7 cells the temporal effects of the AhR agonist benzo[a]pyrene (B[a]P), which is a prototype PAH and known environmental carcinogen. Genes upregulated at least threefold by B[a]P and containing potential XREs within their promoter regions included CYP1A1, CYP1B1, paired box gene 3 (PAX3), cortactin (CTTN/EMS1), β-2-microglobulin [B2M], and transferrin receptor (TfR]. The stimulatory effects of B[a]P on expression of these genes were abrogated by cotreatment with the AhR antagonist flavonoid, α- napthoflavone (ANF). The TfR gene was selected for further analysis as its promoter region contains two potential XREs and its expression has been shown to be increased in breast cancer cells. Accumulation of TfR mRNA in B[a]P-treated cells was confirmed by quantitative real time PCR. Transient transfection studies indicated that the transcriptional activity of the TfR promoter was stimulated by B[a]P, whereas ANF counteracted this induction. These results indicate that the TfR gene may be a potential biomarker of PAH exposure.
AB - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental DNA-damaging agents regarded as risk factors for human disease, including lung and breast cancer. The biotransformation of PAHs to carcinogenic metabolites is mediated by the aromatic hydrocarbon receptor (AhR), which activates transcription at xenobiotic responsive elements (XREs = 5′-GCGTG-3′) found in the promoter regions of genes encoding for detoxifying enzymes, including CYP1A1 and CYP1B1. In this study, we wished to identify novel biomarkers that may be useful in monitoring critical carcinogenic events of the breast induced by PAHs. Using a GeneMAP™ CancerArray, we analyzed in breast cancer MCF-7 cells the temporal effects of the AhR agonist benzo[a]pyrene (B[a]P), which is a prototype PAH and known environmental carcinogen. Genes upregulated at least threefold by B[a]P and containing potential XREs within their promoter regions included CYP1A1, CYP1B1, paired box gene 3 (PAX3), cortactin (CTTN/EMS1), β-2-microglobulin [B2M], and transferrin receptor (TfR]. The stimulatory effects of B[a]P on expression of these genes were abrogated by cotreatment with the AhR antagonist flavonoid, α- napthoflavone (ANF). The TfR gene was selected for further analysis as its promoter region contains two potential XREs and its expression has been shown to be increased in breast cancer cells. Accumulation of TfR mRNA in B[a]P-treated cells was confirmed by quantitative real time PCR. Transient transfection studies indicated that the transcriptional activity of the TfR promoter was stimulated by B[a]P, whereas ANF counteracted this induction. These results indicate that the TfR gene may be a potential biomarker of PAH exposure.
KW - Aromatic hydrocarbon receptor
KW - Benzo[a]pyrene
KW - Breast cancer
KW - Polycyclic aromatic hydrocarbons
KW - Transferrin receptor
UR - http://www.scopus.com/inward/record.url?scp=33747872435&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747872435&partnerID=8YFLogxK
U2 - 10.1002/em.20221
DO - 10.1002/em.20221
M3 - Article
C2 - 16721748
AN - SCOPUS:33747872435
SN - 0893-6692
VL - 47
SP - 518
EP - 526
JO - Environmental and Molecular Mutagenesis
JF - Environmental and Molecular Mutagenesis
IS - 7
ER -