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Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins

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Abstract

Previous studies have demonstrated that the persistent exposure of human bronchial epithelial cells to nicotine (Nic) through nicotinic acetylcholine receptors increases cyclin D1 promoter activity and protein expression. The main purpose of this study is to elucidate the carcinogenic role of cyclin D3, which is involved in breast tumorigenesis when induced by Nic. Real-time PCR analysis revealed that cyclin D3 is highly expressed at the mRNA level in surgically dissected breast tumor tissue, compared to the surrounding normal tissue (tumor/normal fold ratio = 17.93, n = 74). To test whether Nic/nicotinic acetylcholine receptor (nAChR) binding could affect cyclin D3 expression in human breast cancer cells, the transformed cell line MCF-10A-Nic (DOX) was generated from normal breast epithelial cells (MCF-10A) with inducible α9-nAChR gene expression, using the adenovirus tetracycline-regulated Tet-off system. Tet-regulated overexpression of α9-nAChR in MCF-10A-Nic (DOX) xenografted BALB/c-nu/nu mice resulted in a significant induction of cyclin D3. In contrast, cyclin D3 expression was down-regulated in α9-nAChR knock-down (siRNA) MDA-MB-231-xenografted tumors in NOD.CB17-PRKDC(SCID)/J(NOD-SCID) mice. Furthermore, we found that Nic-induced human breast cancer (MDA-MB-231) cell proliferation was inhibited by 1 μM of garcinol (Gar), isolated from the edible fruit Garcinia indica, through down-regulation of α9-nAChR and cyclin D3 expression. These results suggest that α9-nAChR-mediated cyclin D3 overexpression is important for nicotine-induced transformation of normal human breast epithelial cells. The homeostatic regulation of cyclin D3 has the potential to be a molecular target for antitumor chemotherapeutic or chemopreventive purposes in clinical breast cancer patients.

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Abbreviations

AP-1:

Activating protein-1

ChIP:

Chromatin immunoprecipitation analysis

DBM:

Dibenzoylmethane

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethylsulfoxide

DOX:

Doxycycline

FACS:

Fluorescence-activated cell sorter

FAS:

Fetal calf serum

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

Gar:

Garcinol

GUS:

β-Glucuronidase

IHC:

Immunohistochemistry

HDB:

Dibenzoylmethane1-(2-hydroxyphenyl)-3-phenyl-1,3-propanedione

HMDB:

1-(2-Hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

NFκB:

Nuclear factor kappa B

Nic:

Nicotine

nAChR:

Nicotinic acetylcholine receptor

NNK:

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

PBS:

Phosphate-buffered saline

RT-PCR:

Reverse transcriptase polymerase chain reaction

siRNA:

Small interfering RNA

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Acknowledgment

This study was supported by the National Science Council, Grant NSC 95-2320-B-038-016-MY3 to Dr. Ho and NSC 96-2314-B-038-002 to Dr. Wu, and by the Taipei Medical University Hospital (98TMU-TMUH-02-1) to Dr. Yang.

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Authors and Affiliations

  1. Department of Surgery and Center of Quality Management and Breast Health Center, Taipei Medical University, Taipei, Taiwan

    Ching-Shyang Chen, Ching-Shui Huang, Shih-Hsin Tu, Yu-Jia Chang, Po-Li Wei & Yi-Yuan Yang

  2. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

    Chia-Hwa Lee, Chang-Da Hsieh, Li-Ching Chen & Yuan-Soon Ho

  3. Department of Food Science, Rutgers University, New Brunswick, NJ, USA

    Chi-Tang Ho

  4. Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung, Taiwan

    Min-Hsiung Pan

  5. Department of Surgery, Cathay General Hospital, Taipei, Taiwan

    Ching-Shui Huang & Shih-Hsin Tu

  6. Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan

    Ying-Jan Wang

  7. Graduate Institute of Biomedical Technology, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan

    Yi-Yuan Yang & Yuan-Soon Ho

  8. Department of Surgery, School of Medicine, Taipei Medical University-Shuang Ho Hospital, No. 291, Jhongjheng Rd., Jhonghe City, Taipei County, Taiwan

    Chih-Hsiung Wu

  9. Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan

    Yu-Jia Chang, Po-Li Wei, Chih-Hsiung Wu & Yuan-Soon Ho

  10. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan

    Yu-Jia Chang

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  1. Ching-Shyang Chen
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  13. Chih-Hsiung Wu
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  14. Yuan-Soon Ho
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Correspondence to Yi-Yuan Yang, Chih-Hsiung Wu or Yuan-Soon Ho.

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Chia-Hwa Lee and Chang-Da Hsieh contributed equally to this work.

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Chen, CS., Lee, CH., Hsieh, CD. et al. Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins. Breast Cancer Res Treat 125, 73–87 (2011). https://doi.org/10.1007/s10549-010-0821-3

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