Evaluation of 4-aminobiphenyl-DNA adducts in human breast cancer: the influence of tobacco smoke.
Breast cancer is one of the major cancers around the world but its etiology is still not well understood. Only approximately 50% of the disease is associated with known risk factors including highly penetrant genes and lifestyle factors. Thus, environmental carcinogens may play an important role in the etiology of breast cancer. The arylamine 4-aminobiphenyl (4-ABP) is a tobacco smoke constituent, an environmental contaminant, and a well-established bladder carcinogen in rodents and humans. In this study, we investigated the role of 4-ABP in the etiology of human breast cancer by measuring 4-ABP-DNA adducts using a monoclonal antibody based immunoperoxidase method that had been validated by comparison with gas chromatography/mass spectroscopy analysis of liver tissues from 4-ABP-treated mice. Adducts were analyzed in 150 paraffin-embedded breast tumors and in 55 adjacent normal tissues collected from cases in the Long Island Breast Cancer Study Project. The role of polymorphisms in genes involved in the metabolism of 4-ABP including N-acetyl transferase 2 (NAT2), cytochrome P4501A2 (CYP1A2) and glutathione S-transferase M1 (GSTM1) and the nucleotide excision repair gene XPD was also explored in the same patients. The mean log-transformed relative staining intensity for 4-ABP-DNA adducts was higher in normal (5.93 +/- 0.54) than in the corresponding tumor (5.44 +/- 0.62, P < 0.0001) tissues. However, a highly significant positive correlation was observed between the levels of 4-ABP-DNA in both tissues (r = 0.72, P < 0.0001). Smoking status was correlated with the levels of 4-ABP-DNA in tumor adjacent normal tissues with a significant linear trend (P = 0.04) for current, former and never smokers; adducts were not related to smoking status in tumor tissues. No correlation was observed between the levels of 4-ABP-DNA and polymorphisms in the genes analyzed even when subjects were stratified by smoking status. These results demonstrate that smoking is associated with increased levels of 4-ABP-DNA adducts in human mammary tissue. In this study, genetic polymorphisms did not significantly affect the formation of 4-ABP-DNA adducts in breast cancer cases, perhaps due to the small number of samples.
Faraglia
Beatrice
B
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 701 West 168th Street, New York, NY 10032, USA.
Chen
Shu Yuan
SY
Gammon
Marilie D
MD
Zhang
Yujing
Y
Teitelbaum
Susan L
SL
Neugut
Alfred I
AI
Ahsan
Habibul
H
Garbowski
Gail C
GC
Hibshoosh
Hanina
H
Lin
Dongxin
D
Kadlubar
Fred F
FF
Santella
Regina M
RM
D000611:Aminobiphenyl Compounds / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D018736:DNA Adducts / Q000378:metabolism*; D004265:DNA Helicases; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005069:Evaluation Studies as Topic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D011506:Proteins / Q000235:genetics; D012906:Smoke / Q000009:adverse effects*; D014157:Transcription Factors; D051759:Xeroderma Pigmentosum Group D Protein; D014026:Nicotiana
D000611:Aminobiphenyl Compounds; D018736:DNA Adducts; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011506:Proteins; D012906:Smoke; D014157:Transcription Factors; C006757:4-biphenylamine; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human