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

Ching Shyang Chen, Chia-Hwa Lee, Chang Da Hsieh, Chi Tang Ho, Min Hsiung Pan, Ching Shui Huang, Shih-Hsin Tu, Ying Jan Wang, Li-Ching Chen, Yu-Jia Chang, Po-Li Wei, Yi-Yuan Yang, Chih-Hsiung Wu, Yuan-Soon Ho

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)73-87
Number of pages15
JournalBreast Cancer Research and Treatment
Volume125
Issue number1
DOIs
Publication statusPublished - Jan 2011

Fingerprint

Cyclin D3
Nicotinic Receptors
Nicotine
Down-Regulation
Cell Proliferation
Breast Neoplasms
Proteins
Breast
Epithelial Cells
Garcinia
Inbred NOD Mouse
Transformed Cell Line
SCID Mice
garcinol
Cyclin D1
Tetracycline
Adenoviridae
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Fruit

Keywords

  • Breast cancer
  • Cyclin D3
  • Garcinol
  • Nicotinic acetylcholine receptors
  • Smoking

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins. / Chen, Ching Shyang; Lee, Chia-Hwa; Hsieh, Chang Da; Ho, Chi Tang; Pan, Min Hsiung; Huang, Ching Shui; Tu, Shih-Hsin; Wang, Ying Jan; Chen, Li-Ching; Chang, Yu-Jia; Wei, Po-Li; Yang, Yi-Yuan; Wu, Chih-Hsiung; Ho, Yuan-Soon.

In: Breast Cancer Research and Treatment, Vol. 125, No. 1, 01.2011, p. 73-87.

Research output: Contribution to journalArticle

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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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AU - Chang, Yu-Jia

AU - Wei, Po-Li

AU - Yang, Yi-Yuan

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