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Affiliations of authors: Graduate Institute of Medical Sciences, College of Medicine (C-HL, T-CC, L-CC, Y-SH), Department of Medical Technology (C-HL, T-CC, Y-SH), Graduate Institute of Clinical Medicine, College of Medicine (Y-JC), Center of Excellence for Cancer Research (Y-JC, P-LW, C-HW, Y-SH), and Department of Pathology, School of Medicine (J-SC), Taipei Medical University, Taipei, Taiwan; Department of Surgery, Cathay General Hospital, Taipei, Taiwan (C-SH, S-HT); Department of Surgery, School of Medicine (C-SH, C-SC, S-HT, K-WT, P-LW) and Center of Quality Management and Breast Health Center (C-SC), Taipei Medical University Hospital, Taipei, Taiwan; Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan (Y-JW); Department of Surgery, School of Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (C-HW)

Correspondence to:
Yuan-Soon Ho, PhD, Graduate Institute of Biomedical Technology, Taipei Medical University, No. 250 Wu-Hsing St, Taipei 110, Taiwan (e-mail: hoyuansn@tmu.edu.tw) and Chih-Hsiung Wu, MD, PhD, Department of Surgery, School of Medicine, Taipei Medical University-Shuang Ho Hospital, No. 291 Jhongjheng Rd, Jhonghe City, Taipei County 23561, Taiwan (e-mail: chwu@tmu.edu.tw).

Received December 23, 2008.
Revision received July 13, 2010.
Accepted July 14, 2010.

Abstract

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 α9-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 α9-nAChR subunit was inhibited using short interfering RNA. MCF-10A normal human breast epithelial cells were established in which the α9-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, α9-nAChR mRNA was expressed at (mean 7.84-fold) higher levels in breast cancers than in surrounding normal tissue. Stable expression of α9-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 α9 cells = 995.6 mm³, in mice injected with parental cells = 2993.2 mm³, difference = 1997.6 mm³, 95% confidence interval [CI] = 1705 to 2290.2 mm³, 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 α9-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 mm³, difference = 235.4 mm³, 95% CI = 112.7 to 358 mm³, P = .009; DOX−, mean tumor volume without nicotine vs with nicotine = 621.2 vs 898.6 mm³, difference = 277.4 mm³, 95% CI = 98.1 to 456.7 mm³, P = .016; mean tumor volume in the presence of nicotine, DOX+ vs DOX− = 501.6 vs 898.6 mm³, difference = 397 mm³, 95% CI = 241.3 to 552.6 mm³, P = .009).

Conclusion The α9-nAChR is important for nicotine-induced transformation of normal human breast epithelial cells.

fonte science daily:

Nicotine Binding to Receptor Linked to Breast Cancer Cell Growth

ScienceDaily (Aug. 24, 2010) — When nicotine binds to the nicotinic acetylcholine receptor (nAchR), it is known to promote smoking addiction and may also directly promote the development of breast cancer, according to a study published online August 23 in The Journal of the National Cancer Institute.

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While smoking is a well-known risk factor for a broad range of cancer types, non-nicotine components of tobacco have generally been thought to be the carcinogens, so little is known about how nicotine acts on cells to promote cancer cell growth. For breast cancer in particular, some large epidemiological studies have suggested that smoking is related to increased breast cancer risk, but they have not been accompanied by molecular biology studies on how that actually works.

To determine whether nicotine works on the cellular level to promote breast cancer growth, Yuan-Soon Ho, Ph.D., of the Taipei Medical University, and colleagues, looked at 276 breast tumor samples from anonymous donors to the Taipei Medical University Hospital, to see whether subunits of the nicotinic acetylcholine receptor were overexpressed in breast cancer cells compared with surrounding normal cells.

The researchers found that human breast cancer cells consistently overexpressed the alpha 9 subunit of the nAChR (α9-nAchR), and that expression was higher in advanced-stage breast cancer compared with early-stage cancer. They also found that reducing the levels of α9-nAchRs inhibited tumor growth in laboratory experiments, whereas increasing the levels of α9-nAchRs or treating more normal breast cells with nicotine promoted the development of cancer characteristics.

The authors write: "These results imply that receptor-mediated carcinogenic signals play a decisive role in biological functions related to human breast cancer development."

The authors say their study was limited by its small sample size, and the fact that it included only Asian patients. Breast cancer in Taiwan is characterized by its low incidence rate and early stage of tumor onset.

In an accompanying editorial, Ilona Linnoila, M.D., of the Center for Cancer Research at the National Cancer Institute, writes that the study "suggests not only that smoking could be causally related to breast carcinogenesis but also that nicotine could directly contribute to the molecular mechanism of carcinogenesis in addition to indirectly contributing by promoting addiction to smoking."

Furthermore, Linnoila writes, "Better understanding of the molecular mechanisms of the cholinergic pathways will lead to more opportunities for intervention and prevention of tobacco toxicity."

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Journal of the National Cancer Institute, via EurekAlert!, a service of AAAS.

Journal Reference:

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, and Yuan-Soon Ho. Overexpression and Activation of the α9-Nicotinic Receptor During Tumorigenesis in Human Breast Epithelial Cells. Journal of the National Cancer Institute, 2010

:::::: Creato il : 30/10/2010 da Magarotto Roberto :::::: modificato il : 10/11/2010 da Magarotto Roberto ::::::