This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khuri, F. R. Articles by Xu, X.-C. Search for Related Content PubMed PubMed Citation Articles by Khuri, F. R. Articles by Xu, X.-C.

Retinoic Acid Receptor-Beta as a Prognostic Indicator in Stage I Non–Small-Cell Lung Cancer

From the Departments of Thoracic/Head and Neck Medical Oncology, Pathology, Clinical Cancer Prevention, Biostatistics, Medical Informatics, and Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Fadlo R. Khuri, MD, The University of Texas M.D. Anderson Cancer Center, Department of Thoracic/Head and Neck Medical Oncology, 1515 Holcombe Blvd, Box 80, Houston, TX 77030; email fkhuri{at}mdanderson.org

ABSTRACT

PURPOSE: Retinoids are pivotal in the growth and differentiation of certain epithelial tissues, interacting with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors. RAR-beta mRNA is undetectable by in situ hybridization (ISH) in 50% of non–small-cell lung cancers (NSCLC). RAR-ß may suppress tumorigenicity. Therefore, we hypothesized that loss of expression of RAR-ß gene in stage I NSCLC is a prognostic factor of a poor clinical outcome.

PATIENTS AND METHODS: We retrospectively analyzed RAR-ß mRNA levels (by ISH using a digoxigenin-labeled antisense riboprobe) in specimens from 185 consecutive patients with completely resected clinical/radiographic stage I NSCLC for whom clinical follow-up data were available.

RESULTS: One hundred fifty-six patients who met the criteria of pathologic stage I NSCLC and positivity for RXR-alpha mRNA (used as a control to assess RNA degradation) and who had adequate follow-up could be evaluated. RAR-ß mRNA expression was undetectable in 51 patients, weakly positive in 64 patients, and strongly positive in 41 patients. Overall survival of the 41 patients with strongly positive RAR-ß was significantly worse than for the 115 patients with weak or absent RAR-ß (P = .045).

CONCLUSION: Unexpectedly, strong RAR-ß expression was associated with a significantly worse outcome of early-stage NSCLC. The mechanisms underlying this clinically and biologically important finding should be further explored.

This article has been cited by other articles:

				F. R. Khuri, J. J. Lee, S. M. Lippman, E. S. Kim, J. S. Cooper, S. E. Benner, R. Winn, T. F. Pajak, B. Williams, G. Shenouda, et al. Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients. J Natl Cancer Inst, April 5, 2006; 98(7): 441 - 450. [Abstract] [Full Text] [PDF]

				A. L. Sabichi, X. Xu, and S. M. Lippman RAR{beta}1': Primed To Fight Retinoid Resistance in Lung Carcinogenesis J Natl Cancer Inst, November 16, 2005; 97(22): 1632 - 1633. [Full Text] [PDF]

				A. Onn, D. H. Choe, R. S. Herbst, A. M. Correa, R. F. Munden, M. T. Truong, A. A. Vaporciyan, T. Isobe, M. Z. Gilcrease, and E. M. Marom Tumor Cavitation in Stage I Non-Small Cell Lung Cancer: Epidermal Growth Factor Receptor Expression and Prediction of Poor Outcome Radiology, October 1, 2005; 237(1): 342 - 347. [Abstract] [Full Text] [PDF]

				F. Jiang, N. P. Caraway, B. Nebiyou Bekele, H.-Z. Zhang, A. Khanna, H. Wang, R. Li, R. L. Fernandez, T. M. Zaidi, D. A. Johnston, et al. Surfactant Protein A Gene Deletion and Prognostics for Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., August 1, 2005; 11(15): 5417 - 5424. [Abstract] [Full Text] [PDF]

				F. R. Hirsch and S. M. Lippman Advances in the Biology of Lung Cancer Chemoprevention J. Clin. Oncol., May 10, 2005; 23(14): 3186 - 3197. [Abstract] [Full Text] [PDF]

				J. Brabender, R. Metzger, D. Salonga, K. D. Danenberg, P. V. Danenberg, A. H. Holscher, and P. M. Schneider Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer: implications for tumor development and prognosis Carcinogenesis, March 1, 2005; 26(3): 525 - 530. [Abstract] [Full Text] [PDF]

				J. R. Rigas and K. H. Dragnev Emerging Role of Rexinoids in Non-Small Cell Lung Cancer: Focus on Bexarotene Oncologist, January 1, 2005; 10(1): 22 - 33. [Abstract] [Full Text] [PDF]

				C. Lu, J.-C. Soria, X. Tang, X.-C. Xu, L. Wang, L. Mao, R. Lotan, B. Kemp, B. N. Bekele, L. Feng, et al. Prognostic Factors in Resected Stage I Non-Small-Cell Lung Cancer: A Multivariate Analysis of Six Molecular Markers J. Clin. Oncol., November 15, 2004; 22(22): 4575 - 4583. [Abstract] [Full Text] [PDF]

				F. R. Khuri and R. Lotan Retinoids in Lung Cancer: Friend, Foe, or Fellow Traveler? J. Clin. Oncol., September 1, 2004; 22(17): 3435 - 3437. [Full Text] [PDF]

				J. S. Kim, H. Lee, H. Kim, Y. M. Shim, J. Han, J. Park, and D.-H. Kim Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non-Small-Cell Lung Cancer J. Clin. Oncol., September 1, 2004; 22(17): 3443 - 3450. [Abstract] [Full Text] [PDF]

				F. R. Khuri and V. Cohen Molecularly Targeted Approaches to the Chemoprevention of Lung Cancer Clin. Cancer Res., June 15, 2004; 10(12): 4249S - 4253S. [Abstract] [Full Text] [PDF]

				D. G. Pfister, D. H. Johnson, C. G. Azzoli, W. Sause, T. J. Smith, S. Baker Jr, J. Olak, D. Stover, J. R. Strawn, A. T. Turrisi, et al. American Society of Clinical Oncology Treatment of Unresectable Non-Small-Cell Lung Cancer Guideline: Update 2003 J. Clin. Oncol., January 15, 2004; 22(2): 330 - 353. [Full Text] [PDF]

				A. Onn, A. M. Correa, M. Gilcrease, T. Isobe, E. Massarelli, C. D. Bucana, M. S. O'Reilly, W. K. Hong, I. J. Fidler, J. B. Putnam, et al. Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-neu Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., January 1, 2004; 10(1): 136 - 143. [Abstract] [Full Text] [PDF]

				J.-C. Soria, C. Moon, B. L. Kemp, D. D. Liu, L. Feng, X. Tang, Y.-S. Chang, L. Mao, and F. R. Khuri Lack of Interleukin-10 Expression Could Predict Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., May 1, 2003; 9(5): 1785 - 1791. [Abstract] [Full Text] [PDF]

				J.-C. Soria, X. Xu, D. D. Liu, J. J. Lee, J. Kurie, R. C. Morice, F. Khuri, L. Mao, W. K. Hong, and R. Lotan Retinoic Acid Receptor {beta} and Telomerase Catalytic Subunit Expression in Bronchial Epithelium of Heavy Smokers J Natl Cancer Inst, January 15, 2003; 95(2): 165 - 168. [Abstract] [Full Text] [PDF]

				Y. S. Chang, L. Wang, D. Liu, L. Mao, W. K. Hong, F. R. Khuri, and H.-Y. Lee Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3669 - 3675. [Abstract] [Full Text] [PDF]

				L. Wang, J.-C. Soria, B. L. Kemp, D. D. Liu, L. Mao, and F. R. Khuri hTERT Expression Is a Prognostic Factor of Survival in Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., September 1, 2002; 8(9): 2883 - 2889. [Abstract] [Full Text] [PDF]

				F. McGregor, A. Muntoni, J. Fleming, J. Brown, D. H. Felix, D. G. MacDonald, E. K. Parkinson, and P. R. Harrison Molecular Changes Associated with Oral Dysplasia Progression and Acquisition of Immortality: Potential for Its Reversal by 5-Azacytidine Cancer Res., August 15, 2002; 62(16): 4757 - 4766. [Abstract] [Full Text] [PDF]

				E. F. Farias, A. Arapshian, I. J. Bleiweiss, S. Waxman, A. Zelent, and R. Mira-y-Lopez Retinoic Acid Receptor {alpha}2 Is a Growth Suppressor Epigenetically Silenced In MCF-7 Human Breast Cancer Cells Cell Growth Differ., August 1, 2002; 13(8): 335 - 341. [Abstract] [Full Text] [PDF]

				J. Brabender, K. D. Danenberg, R. Metzger, P. M. Schneider, R. V. Lord, S. Groshen, D. D. Tsao-Wei, J. Park, D. Salonga, A. H. Holscher, et al. The Role of Retinoid X Receptor Messenger RNA Expression in Curatively Resected Non-Small Cell Lung Cancer Clin. Cancer Res., February 1, 2002; 8(2): 438 - 443. [Abstract] [Full Text] [PDF]

				V. Vivat-Hannah, D. You, C. Rizzo, J.-P. Daris, P. Lapointe, F. C. Zusi, A. Marinier, M. V. Lorenzi, and M. M. Gottardis Synergistic Cytotoxicity Exhibited by Combination Treatment of Selective Retinoid Ligands with Taxol (Paclitaxel) Cancer Res., December 1, 2001; 61(24): 8703 - 8711. [Abstract] [Full Text] [PDF]

				S. M. Lippman and M. R. Spitz Lung Cancer Chemoprevention: An Integrated Approach J. Clin. Oncol., September 15, 2001; 19(90001): 74s - 82. [Abstract] [Full Text] [PDF]

				S. M. Lippman, J. J. Lee, D. D. Karp, E. E. Vokes, S. E. Benner, G. E. Goodman, F. R. Khuri, R. Marks, R. J. Winn, W. Fry, et al. Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer J Natl Cancer Inst, April 18, 2001; 93(8): 605 - 618. [Abstract] [Full Text] [PDF]

				R. Pili, M. P. Kruszewski, B. W. Hager, J. Lantz, and M. A. Carducci Combination of Phenylbutyrate and 13-cis Retinoic Acid Inhibits Prostate Tumor Growth and Angiogenesis Cancer Res., February 1, 2001; 61(4): 1477 - 1485. [Abstract] [Full Text]

				W. K. Hong, M. R. Spitz, and S. M. Lippman Cancer Chemoprevention in the 21st Century: Genetics, Risk Modeling, and Molecular Targets J. Clin. Oncol., November 1, 2000; 18(90001): 9s - 18. [Full Text] [PDF]