Journal article

Publication year: 2011

Pages: 546-552

Journal: International Journal of Cancer

Volume number: 129

Issue number: 3

ISSN: 0020-7136

eISSN: 1097-0215

Open access status: Bronze

DOI Link: https://doi.org/10.1002/ijc.25958

Publisher: Wiley

Abstract: 
Several molecular changes in colorectal adenomas provide the basis of the adenoma-carcinoma sequence. We investigated the expression of xenobiotic ATP-binding cassette (ABC) transporters in humans and in ApcMin mice and conducted functional studies estimating the importance of the expression changes. Twenty-nine adenomas from 21 patients and eight adenomas from four ApcMin mice were analyzed using Western blotting and quantitative Real-time polymerase chain reaction (RT-PCR). Adjacent healthy tissue served as control for each polyp. Breast cancer resistance protein (BCRP) was significantly downregulated in human colorectal adenomas (to 28 +/- 35% of adjacent healthy tissue). This was in line with data from ApcMin mice adenomas, where downregulation was significant as well (to 58 +/- 34%). In parallel, quantitative RT-PCR showed BCRP mRNA downregulation in human adenomas (to 17 +/- 31%). Basal multidrug resistance-associated protein 2 expression was low and did not change in adenomas; multidrug resistance transporter 1 expression also did not differ between adenomas and healthy tissue. In a functional study, ApcMin mice received radioactively labelled 2-amino-1-methyl-6-phenylimidazo[4,5-beta] pyridine (PhIP), a food colon carcinogen and substrate of BCRP, by oral gavage with analysis of PhIP accumulation and DNA adduct formation 48 hr later. In this setting, we could demonstrate a higher carcinogen concentration in adenomas of ApcMin mice (181 +/- 113% of normal tissue) including immunohistochemical detection of PhIP-DNA adducts. We conclude that significant transcriptional downregulation of BCRP/Bcrp leads to higher carcinogen concentrations in colorectal adenomas of mice and men. This might promote the adenoma-carcinoma sequence by higher genotoxic effects. The results indicate a possible role of transporter deficiencies in susceptibility for colon carcinoma.

Harvard Citation style: Dietrich, C., Vehr, A., Martin, I., Gassler, N., Rath, T., Roeb, E., et al. (2011) Downregulation of Breast Cancer Resistance Protein in colon adenomas reduces cellular xenobiotic resistance and leads to accumulation of a food-derived carcinogen, International Journal of Cancer, 129(3), pp. 546-552. https://doi.org/10.1002/ijc.25958

APA Citation style: Dietrich, C., Vehr, A., Martin, I., Gassler, N., Rath, T., Roeb, E., Schmitt, J., Trautwein, C., & Geier, A. (2011). Downregulation of Breast Cancer Resistance Protein in colon adenomas reduces cellular xenobiotic resistance and leads to accumulation of a food-derived carcinogen. International Journal of Cancer. 129(3), 546-552. https://doi.org/10.1002/ijc.25958