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This article is part of the supplement: Proceedings of the 2012 Sino-American Symposium on Clinical and Translational Medicine (SAS-CTM)

Open Access Meeting abstract

Targeting androgen receptor as a new potential therapeutic approach to battle tobacco carcinogens-induced non-small cell lung cancer

Shauh-Der Yeh12*, Pan-Chyr Yang2, Hsuan-Hsuan Lu1, Chawnshang Chang13* and Cheng-Wen Wu2

Author Affiliations

1 Department of Urology and Center of Excellence for Cancer Research, Taipei Medical University and Hospital, Taipei, 110, Taiwan

2 Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan

3 Department of Pathology, University of Rochester, Rochester, NY 14642, USA

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Journal of Translational Medicine 2012, 10(Suppl 2):A8  doi:10.1186/1479-5876-10-S2-A8


The electronic version of this article is the complete one and can be found online at: http://www.translational-medicine.com/content/10/S2/A8


Published:17 October 2012

© 2012 Yeh et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer. The incidence and prognosis in NSCLC demonstrates gender difference [1,2]; therefore, sex steroids and/or their receptors may play important roles during lung tumorigenesis and cancer progression. In our previous investigation, cell proliferation, migration, invasion, and tumor formation were inhibited by shRNA interference of androgen receptor (AR) in non-small cell lung cancer (NSCLC) cells lines. The expressions of cyclin D1 also decreased to less than 50% after AR knockdown. However, the roles of androgen receptor in treatment of NSCLC are still controversial.

Materials and methods

To validate therapeutic effects of targeting androgen receptor on NSCLC, initially we administered 8 doses of tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP), to induce lung tumor growth in female A/JB6.129-Arlox Tg(Mx1-cre)1Cgn mice when they were 5 weeks old. In the next step, targeted Ar gene disruption was induced with 6 doses of polyinosinic: polycytidylic acid (polyI:C) intraperitoneal injection in Mx1-cre+ mice when they were 26 weeks old. We also performed 6 doses of normal saline injection to NNK+BaP-treated female A/JB6.129-Arlox Tg(Mx1-cre)1Cgn mice in the same time point for the control group. Finally, all mice were sacrificed in 31 weeks old and total lung nodules and tumor larger than 1 mm in diameter were calculated under dissection microscope.

Results

In immunohistochemical studies, AR expression in lung was deficient in Mx1-cre+ mice after polyI:C treatment. Pulmonary expression of cyclin D1 was also suppressed in polyI:C treated Mx1-cre+ mice. The number of total nodules in bilateral lungs from polyI:C treated Mx1-cre+ mice (n=8) was 7.375 ± 5.476 (mean ± S.E.). In comparison, the total number of lung nodules from normal saline treated Mx1-cre+ mice (n=8) was 14.375 ± 7.269 (p= 0.0456, 95% CIs on the mean = 9.235 to 19.515). The number of large nodules (>1 mm in diameter) in bilateral lungs was 1.375 ± 1.188 in polyI:C treated Mx1-cre+ mice and 6.25 ± 4.464 in normal saline treated Mx1-cre+ control mice (p= 0.00492, 95% CIs on the mean = 3.093 to 9.407). Deficient AR expression through inducible disruption of Ar gene could reduce lung tumor multiplicity and further inhibit tumor progression (decrease tumor volume) in tobacco carcinogens-induced lung tumorigenesis model.

Conclusions

Our data indicate that androgen receptor warrants consideration as a novel therapeutic target for NSCLC in a clinical lung cancer treatment trial.

References

  1. Sekine I, Sumi M, Ito Y, et al.: Gender difference in treatment outcomes in patients with stage III non-small cell lung cancer receiving concurrent chemoradiotherapy.

    Jpn J Clin Oncol 2009, 39:707-712. PubMed Abstract | Publisher Full Text OpenURL

  2. Sakurai H, Asamura H, Goya T, et al.: Survival differences by gender for resected non-small cell lung cancer: a retrospective analysis of 12,509 cases in a Japanese Lung Cancer Registry study.

    J Thorac Oncol 2010, 5:1594-1601. PubMed Abstract | Publisher Full Text OpenURL