Document Detail

Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells.
MedLine Citation:
PMID:  20733118     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Large epidemiological cohort studies in the United States have indicated that active and passive smoking are associated with increased breast cancer risk. However, there was no direct evidence of an effect of tobacco carcinogens on the cellular molecules involved in breast tumorigenesis. METHODS: Reverse transcription-polymerase chain reaction was used to determine the expression of all of the nicotinic acetylcholine receptor (nAChR) subunits in 50 human breast cancer samples and to determine the expression of the alpha9-nAChR subunit in 276 surgical and laser capture microdissected breast tumor vs normal tissue pairs. Stable MDA-MB-231 breast cancer cell lines were established in which expression of the alpha9-nAChR subunit was inhibited using short interfering RNA. MCF-10A normal human breast epithelial cells were established in which the alpha9-nAChR subunit could be conditionally overexpressed by removal of doxycycline from the culture fluid. Cell proliferation and soft agar assays and tumor growth in nude mice were used as measures of cell transformation. All statistical tests were two-sided. RESULTS: In 186 (67.3%) of the 276 paired samples, alpha9-nAChR mRNA was expressed at (mean 7.84-fold) higher levels in breast cancers than in surrounding normal tissue. Stable expression of alpha9-nAChR short interfering RNA in MDA-MB-231 cells attenuated nicotine-stimulated proliferation and growth in soft agar and reduced tumor volume when the cells were introduced as xenografts in SCID mice (n = 5 mice per group; mean tumor volume at 6 weeks treatment in mice injected with Si alpha9 cells = 995.6 mm(3), in mice injected with parental cells = 2993.2 mm(3), difference = 1997.6 mm(3), 95% confidence interval [CI] = 1705 to 2290.2 mm(3), P = .009). Long-term treatment of MCF-10A normal breast epithelial cells with either nicotine or its active metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, triggered precancerous transformation as defined by soft agar assay. Inducible overexpression of alpha9-nAChR in MCF-10A cell xenografts in nude mice substantially increased tumor growth (n = 5 mice per group; DOX+, mean tumor volume without nicotine vs with nicotine = 266.2 vs 501.6 mm(3), difference = 235.4 mm(3), 95% CI = 112.7 to 358 mm(3), P = .009; DOX-, mean tumor volume without nicotine vs with nicotine = 621.2 vs 898.6 mm(3), difference = 277.4 mm(3), 95% CI = 98.1 to 456.7 mm(3), P = .016; mean tumor volume in the presence of nicotine, DOX+ vs DOX- = 501.6 vs 898.6 mm(3), difference = 397 mm(3), 95% CI = 241.3 to 552.6 mm(3), P = .009). CONCLUSION: The alpha9-nAChR is important for nicotine-induced transformation of normal human breast epithelial cells.
Chia-Hwa Lee; Ching-Shui Huang; Ching-Shyang Chen; Shih-Hsin Tu; Ying-Jan Wang; Yu-Jia Chang; Ka-Wai Tam; Po-Li Wei; Tzu-Chun Cheng; Jan-Show Chu; Li-Ching Chen; Chih-Hsiung Wu; Yuan-Soon Ho
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-23
Journal Detail:
Title:  Journal of the National Cancer Institute     Volume:  102     ISSN:  1460-2105     ISO Abbreviation:  J. Natl. Cancer Inst.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-08     Completed Date:  2010-09-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7503089     Medline TA:  J Natl Cancer Inst     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1322-35     Citation Subset:  IM    
Graduate Institute of Biomedical Technology, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei, Taiwan.
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MeSH Terms
Blotting, Western
Breast / metabolism*
Breast Neoplasms / metabolism*
Cell Line, Tumor
Cell Proliferation
Epithelial Cells / metabolism*
Gene Expression Regulation, Neoplastic
Mice, Nude
Microscopy, Confocal
RNA, Small Interfering / metabolism
Receptors, Nicotinic / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Risk Factors
Smoking / adverse effects*,  metabolism*
Tobacco Smoke Pollution / adverse effects
Transplantation, Heterologous
Reg. No./Substance:
0/RNA, Small Interfering; 0/Receptors, Nicotinic; 0/Tobacco Smoke Pollution; 0/nAChR alpha9
Comment In:
J Natl Cancer Inst. 2010 Sep 8;102(17):1298-9   [PMID:  20733119 ]

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