© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 15, 1317-1321,
August 4, 1999
© 1999 Oxford University Press
REPORTS |
Nuclear Retinoid Acid Receptor Beta in Bronchial Epithelium of Smokers Before and During Chemoprevention
Affiliations of authors: X.-C. Xu, X. Liu, S. M. Lippman (Department of Clinical Cancer Prevention), J. S. Lee, R. C. Morice, W. K. Hong, R. Lotan (Department of Thoracic/Head and Neck Medical Oncology), J. J. Lee (Department of Biomathematics), The University of Texas M. D. Anderson Cancer Center, Houston.
Correspondence to: Reuben Lotan, Ph.D., Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: rlotan{at}notes.mdacc.tmc.edu).
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ABSTRACT |
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BACKGROUND: Retinoids can reverse neoplastic lesions and prevent second primary tumors in the aerodigestive tract. These effects are thought to be mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each receptor group including three subtypes (
,
ß, and 
). Previously, we found that RARß expression was suppressed in lung
cancer. In this study, we investigated whether expression of RARß is modulated by
chemopreventive intervention. METHODS: Using in situ hybridization, we analyzed
RARß messenger RNA (mRNA) expression in bronchial biopsy specimens from heavy
smokers, at baseline and after 6 months of treatment with 13-cis-retinoic acid (13-cis-RA) or placebo. Since we had previously detected RARß expression in 90%
of
bronchial specimens from nonsmokers, we considered loss of RARß mRNA expression in at
least one of six biopsy specimens at baseline in this study to be aberrant. RESULTS: RARß
mRNA expression was aberrant in 30 (85.7%) of 35 subjects in the 13-cis-RA
group and in 24 (72.7%) of 33 subjects in the placebo group. After 6 months of 13-cis-RA treatment, the number of subjects who were RARß positive in all six biopsy
specimens increased from five of 35 to 13 of 35 (2.6-fold), so that the percentage of individuals
with aberrant RARß expression decreased to 62.9% (22 of 35), which represents a
statistically significant difference from baseline expression (two-sided P = .01).
In
the placebo group, no statistically significant difference in RARß expression was observed
between baseline and 6 months. RARß expression was not related to current smoking status
or reversal of squamous metaplasia. CONCLUSIONS: These results indicate that RARß is
an independent marker of response to 13-cis-RA and may serve as an intermediate
biomarker in chemoprevention trials of upper aerodigestive tract cancers.
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INTRODUCTION |
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Lung cancer is the most common neoplasia worldwide (1). As the leading cause of cancer death in the United States, lung cancer accounts for 28.6% of all cancer mortality and 7% of all deaths. It has been estimated that there were 171 500 new cases and 160 100 deaths from lung cancers in the United States in 1998 (2). Lung cancer incidence is increasing in both men and women, and the mortality from it has surpassed that of breast cancer in women and of prostate cancer in men. Unfortunately, the overall 5-year survival rate is under 14%, despite advances in a variety of therapeutic modalities, including surgery, radiotherapy, and chemotherapy (1,2). Therefore, the development of new strategies for the prevention and treatment of lung cancer is urgently needed. One possible approach is chemoprevention, an intervention into the carcinogenesis process prior to the development of a locally invasive cancer (3). Among the chemopreventive agents examined for effects on lung cancer, retinoids—including retinoic acid (RA)-appear to have the potential for chemoprevention of upper aerodigestive tract cancers (3-5).
Vitamin A deficiency has been associated with bronchial metaplasia and increased lung
cancer
incidence (4,5). Retinoids regulate differentiation of airway epithelium in vitro (6) and suppress carcinogenesis in animal models of
lung
cancer (5,7). These effects of retinoids are thought to be mediated by
nuclear retinoid receptors, which belong to the steroid/thyroid hormone superfamily. Like other
members of this family, these receptors are ligand-activated, DNA-binding, trans-activating, transcription-modulating proteins. Two types of receptor have been identified:
retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Each type includes three
subtypes of RAR (, ß, and ) and of RXR (, ß, and ), with distinct
amino- and carboxyl-terminal domains (8,9). Each subtype is thought to
regulate the expression of distinct genes (8,9).
Aberrant expression of the nuclear retinoid receptors may result in an abrogated retinoid signaling pathway. Indeed, we (10) and others (11-14) have demonstrated that RARß expression is suppressed in both lung cancer tissues and cell lines, and this finding suggested that the decreased expression of this receptor is associated with lung carcinogenesis. However, RARß expression in bronchial epithelium from heavy smokers has not been studied, nor was the effect on smokers of treatment with retinoids. Therefore, in this study, we used bronchial biopsy specimens from chronic smokers before and after treatment with 13-cis-RA or placebo (15) to evaluate RARß expression and its modulation by treatment.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionNotesReferences |
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Surgical Specimens
This retrospective study used tissue specimens that were available from a previous clinical trial conducted at The University of Texas M. D. Anderson Cancer Center, Houston (15) In this trial, 152 smokers were evaluated prospectively with bronchoscopy, and biopsy specimens were obtained from six predetermined anatomic sites located in the bronchus of each lobe plus the main carina of each subject. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg body weight of 13-cis-RA (isotretinoin provided by Hoffmann-La Roche Inc., Nutley, NJ) or placebo daily for 6 months. Of the 86 subjects, 41 were randomly assigned to the 13-cis-RA and 45 to the placebo group. Only 69 of the subjects were re-evaluated after a second bronchoscopy, with six biopsies performed at the completion of treatment to determine the metaplasia index, whereas the rest of the subjects did not complete the planned 6-month treatment because of various reasons, including refusal of treatment, loss to follow-up, toxic effects, and intercurrent illness (15).
Bronchial biopsy specimens available for analysis of retinoid receptors in this study were obtained at baseline and after 6 months of treatment from 68 patients (specimens from the 69th patient were used up in another study), 35 of whom received 13-cis-RA and 33 of whom received placebo (15). The specimens were fixed in 10% neutral formalin and embedded in paraffin at the Department of Pathology, The University of Texas M. D. Anderson Cancer Center. All of the specimens were cut into 4-µm-thick sections and one section was stained with hematoxylin-eosin for pathologic diagnosis, whereas the other consecutive sections were processed for retinoid receptor analysis by use of messenger RNA (mRNA) in situ hybridization technique that we described previously (16).
In Situ Hybridization
A nonradioactive, in situ hybridization technique by use of digoxigenin-labeled
antisense riboprobes or RARß and RXR was used to analyze nuclear retinoid receptors
in formalin-fixed, paraffin-embedded tissue sections as described in detail elsewhere (16). The quality and specificity of the digoxigenin-labeled probes were determined
with northern blotting, and the specificity of the binding of antisense riboprobes was verified by
use of sense probes as controls (16). To exclude any potential bias in the
scoring of the RARß expression, the hybridization procedure was done on samples that were
coded so that the person who performed the analysis did not know whether the samples were
from treated subjects or from the placebo group and whether they were obtained at baseline or at
6 months. The stained sections were reviewed and scored by use of an Olympus Microscope
(Olympus America, Melville, NY).
Statistical Analysis
RARß expression was measured in each of the six prespecified biopsy sites for each
patient. Because the loss of RARß expression is an abnormal event, we considered a patient
as having an aberrant RARß expression status if at least one of the six sites has lost
RARß. All of the analyses were performed with each subject serving as the unit of analysis.
Measures of RARß and RXR expression were assigned as positive or negative staining
only. The McNemar test (17) was performed to determine the change in
the aberrant RARß expression before and after treatment. The method of generalized
estimating equations with binary outcome and logistic link was applied to the data to compare
change in the aberrant RARß between the treatment groups. Analysis of variance was used
to
examine whether the reduction in metaplasia index is related to changes in RARß status. All
reported P values were two-sided. A test was considered statistically significant when P<.05.
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RESULTS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionNotesReferences |
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The characteristics of subjects from whom specimens were available for this study are shown in Table 1.
Sections from
six sites in the lungs of each case subject were placed on two glass
slides for in situ hybridization to detect RARß, and
adjacent sections were used to detect RXR. We found the latter
receptor to be ubiquitous in lung and to be expressed in both normal
and malignant lung epithelia (10). We used it here as a
control for the presence of undegraded RNA in a section to exclude
false-negative data in the RARß analysis in the adjacent section.
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Representative examples of the in situ hybridization results are shown in Fig. 1.
The presence of receptor mRNA is indicated by purple staining of the
cytoplasm of cells in biopsy sections incubated with antisense riboprobe. Normal bronchial
epithelium from nonsmokers was available from a previous study (10)
and
was positive for RARß, as shown in Fig. 1, A (upper left panel),
whereas no RARß mRNA was detected in a section of a bronchial biopsy taken at baseline
from a smoker enrolled in the clinical trial (Fig. 1, A, middle left panel).
In
contrast, RARß was detected in a section of a biopsy taken from the same patient after 6
months of 13-cis-RA treatment (Fig. 1, A, bottom left panel).
Biopsy specimens taken both at baseline and after placebo treatment were negative for
RARß
(Fig. 1, B, upper and lower panels, respectively). All specimens were
positive for RXR mRNA, indicating that degradation of mRNA could not account for the
lack of staining with RARß antisense probes. Sense RARß riboprobes did not stain the
sections (data not shown), indicating that the staining with antisense riboprobes was specific.
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In previous studies (10,18,19) with visually identifiable, nonmalignant oral lesions, head and neck cancers, and lung cancers, we usually collected a single biopsy specimen per subject at baseline and another after treatment. Therefore, it was straightforward in such a study to classify a subject as being either positive or negative for RARß expression. However, in this study, we collected bronchial tissue biopsy specimens from six different loci in the bronchial tree per subject, both at baseline and after treatment, and the analyses of individual biopsy specimens in the same subject did not always give the same results. Because our previous studies have demonstrated that normal bronchial epithelial tissues from more than 90% of nonsmoker's lungs were positive for RARß mRNA (10), we considered a subject to have an aberrant RARß expression if even one of six biopsy specimens was negative. Table 2
shows the results of the RARß
analyses. Aberrant RARß expression was detected at baseline in 30 (85.7%) of 35
subjects in the 13-cis-RA group and in 24 (72.7%) of 33 subjects in the placebo
group. For an unknown reason, although the subjects in the clinical trial (15) were randomly assigned to receive either placebo or 13-cis-RA, the latter
group had a slightly higher percentage of aberrant RARß expression at baseline compared
with the former group. The difference between the two groups was not statistically significant (P = .19).
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After 6 months of 13-cis-RA treatment, the number of RARß-positive subjects (in whom all six biopsy specimens were positive for RARß) increased 2.6-fold (from five of 35 to 13 of 35). In contrast, in the placebo group, the number of RARß-positive subjects increased by only 1.1-fold (from nine of 33 to 10 of 33) (Table 2)
. When
the data were analyzed as changes in aberrant RARß, the percentage of subjects with an
aberrant RARß expression in the 13-cis-RA group decreased by 26.6%
(from
85.7% at baseline to 62.9% at 6 months), and the change was statistically
significant
(P = .01). In contrast, in the placebo group, the percentage of subjects with
aberrant RARß expression was reduced by only 4.1% (from 72.7% to
69.7% ), and there was no statistically significant difference in RARß expression
between baseline and 6 months (Table 2). The difference in the change in
RARß expression between the 13-cis-RA group and the placebo group was
compared with the use of the generalized estimating equations methods and was found not to be
statistically significant (P = .09).
All specimens expressed RXR at baseline and after treatment with either placebo or 13-cis-RA (data not shown). Sixteen subjects quit smoking at 6 months, whereas the
remaining 52 subjects continued to smoke. The transition from aberrant to normal RARß
expression from baseline to 6 months was observed in two of the quitters and in seven
(13.5%) of the persistent smokers. RARß expression was not related to smoking
status change at 6 months (P = .52).
The change in RARß expression was also not associated with the reversal of squamous metaplasia. The decrease in metaplasia index (95% bootstrap bias-corrected accelerated percentile interval; n = number of subjects) was 8.8 (1.9, 15.1; n = 40), 7.6 (-5.3, 17.8; n = 14), 8.8 (-5.9, 37.7; n = 5), and 1.7 (-16.9, 33.6; n = 9) among subjects with (+, +), (+, -), (-, +), or (-, -) aberrant RARß at baseline and at 6 months, respectively. The difference was not statistically significant (P = .90).
There was no association between the presence or absence of metaplasia at baseline and the expression of RARß at baseline or the increase in RARß after 6 months. For example, RARß was increased in 34 (54.0%) of 63 sites that did not have metaplasia at baseline (histologically normal) and in 26 (70.3%) of 37 sites that had metaplasia at baseline (chi-squared P = .11).
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DISCUSSION |
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In this study, we have demonstrated for the first time to our knowledge that RARß expression is suppressed in biopsy specimens of bronchial epithelium from chronic smokers who were selected for the presence of dysplasia or metaplasia and that the receptor's expression increases after a 6-month treatment with 13-cis-RA in vivo. Because of the limited number of samples, the difference in the degree of increased RARß expression between the 13-cis-RA group and the placebo group (26.6% versus 4.1%) is only marginally significant (P = .09). It is noteworthy that, when we analyzed the data after considering a subject to be RARß positive if even one of the six biopsy specimens was positive, then the P value of treatment difference in increased expression of RARß was .02 instead of .09. However, we did not choose the classification of RARß status of a subject to show the best result; instead, we have chosen it on the basis of the biologic reasoning that RARß positivity is the normal state. Therefore, a loss of RARß expression in even one biopsy specimen should classify the subject as having an aberrant RARß expression.
An increase in RARß expression was not associated with a reduction in the bronchial metaplasia index or with smoking cessation. The present findings—and our previous data on receptor expression in non-small-cell lung cancers (10)—are reminiscent of our previous observations in oral nonmalignant lesions (18) and head and neck cancers (19), in that the decrease in RARß expression occurred at early stages of carcinogenesis and could be reversed in some cases by 13-cis-RA treatment.
We used in situ hybridization for RARß analysis because antibodies obtained from commercial and other sources appeared to cross-react with several protein bands on western blotting of lung cancer cell lines and normal bronchial epithelial cells (unpublished data).
Loss of RARß mRNA expression has been observed in a variety of lung cancer cell lines (11-14), and it has been suggested that this loss may contribute to lung carcinogenesis. A potential role for RARß in the suppression of lung cancer development has been further supported by the reports on the loss of tumorigenicity in nude mice by human lung cancer cells expressing a transfected RARß (20) and the observation that transgenic mice expressing antisense RARß2 developed lung cancer (21). The selective suppression of RARß expression may be related to the process of malignant transformation in the lung (10-14,20,21) and may lead to resistance to growth inhibition by RA (12,14,22). The loss of RARß expression in the bronchial epithelium may be related to aberrations in the retinoid-signaling pathway because of changes in co-activators (9) or in other receptors, such as nuclear receptor 77 (nur77) or chicken ovalbumin upstream promoter-transcription factor (22).
The mechanism by which RARß expression is increased in biopsy specimens from subjects treated with 13-cis-RA is not clear; it may be due to restoration of a more normal phenotype to the abnormal epithelium by the retinoid, induction of RARß by activation of the RA response element in the RARß promoter (8,9), or elimination of RARß-negative cells and their replacement by normal RARß-positive cells during the 6-month treatment with 13-cis-RA. The reason why 13-cis-RA treatment did not increase RARß expression in all of the samples is not known. It is possible that in some subjects, the RARß-negative cells have severe defects in retinoid signaling that prevent even pharmacologic levels of retinoid from inducing RARß. Studies with lung cancer cell lines (14,22) have demonstrated defects in induction of RARß.
Intermediate biomarkers are needed to evaluate the end point of chemoprevention (23). Bronchial metaplasia is one of the earliest and reversible changes reflecting chronic irritation (cigarette smoking) or vitamin A deficiency (24,25). Previous studies (22,25-27) suggested the use of bronchial metaplasia as a biomarker in lung cancer chemoprevention, but this marker has not been validated or shown to be associated with long-term cancer development. Furthermore, complete reversal of squamous metaplasia was noted in both placebo and 13-cis-RA groups (15). In both groups, smoking cessation resulted in statistically significant declines in the extent of squamous metaplasia, whereas no statistically significant change in metaplasia index was found among those who continued to smoke. Thus, 13-cis-RA had no effect on squamous metaplasia, a candidate intermediate end point of bronchial carcinogenesis.
On the basis of our previous (10) and present studies, we propose to use RARß as an intermediate biomarker for lung cancer chemoprevention trials, especially when retinoids are used as the chemopreventive agents, because its expression is suppressed in the field of carcinogenesis and is increased by 13-cis-RA in a fashion that is independent of squamous metaplasia and cigarette smoking status. Because of the limited sample size of this study, the full potential of using RARß in chemoprevention trials needs to be validated by larger prospective studies in the future.
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NOTES |
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Supported by Public Health Service grant U19CA68437 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. W. K. Hong is an American Cancer Society Clinical Research Professor. R. Lotan is the incumbent of the Irving and Nadine Mansfield and Robert David Levitt Cancer Research Chair.
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Manuscript received November 3, 1998; revised May 17, 1999; accepted May 27, 1999.
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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]
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 F. R. Khuri, H. Wu, J. J. Lee, B. L. Kemp, R. Lotan, S. M. Lippman, L. Feng, W. K. Hong, and X.-C. Xu Cyclooxygenase-2 Overexpression Is a Marker of Poor Prognosis in Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., April 1, 2001; 7(4): 861 - 867. [Abstract] [Full Text]
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A. F. Gazdar, S. Zochbauer-Moller, A. Virmani, J. Kurie, J. D. Minna, and S. Lam RESPONSE: Re: Promoter Methylation and Silencing of the Retinoic Acid Receptor-{{beta}} Gene in Lung Carcinomas J Natl Cancer Inst, January 3, 2001; 93(1): 67 - 68. [Full Text] [PDF]
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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]
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F. R. Khuri, R. Lotan, B. L. Kemp, S. M. Lippman, H. Wu, L. Feng, J. J. Lee, C. S. Cooksley, B. Parr, E. Chang, et al. Retinoic Acid Receptor-Beta as a Prognostic Indicator in Stage I Non-Small-Cell Lung Cancer J. Clin. Oncol., August 15, 2000; 18(15): 2798 - 2804. [Abstract] [Full Text] [PDF]
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J. M. Kurie, J. S. Lee, F. R. Khuri, L. Mao, R. C. Morice, J. J. Lee, G. L. Walsh, A. Broxson, S. M. Lippman, J. Y. Ro, et al. N-(4-Hydroxyphenyl)Retinamide in the Chemoprevention of Squamous Metaplasia and Dysplasia of the Bronchial Epithelium Clin. Cancer Res., August 1, 2000; 6(8): 2973 - 2979. [Abstract] [Full Text]
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 A. TOULOUSE, M. LOUBEAU, J. MORIN, J. J. PAPPAS, J. WU, and W. E. C. BRADLEY RAR{beta} involvement in enhancement of lung tumor cell immunogenicity revealed by array analysis FASEB J, June 1, 2000; 14(9): 1224 - 1232. [Abstract] [Full Text]
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Y. Zhang, A. K. Rishi, M. I. Dawson, R. Tschang, L. Farhana, M. Boyanapalli, U. Reichert, B. Shroot, E. C. Van Buren, and J. A. Fontana S-phase Arrest and Apoptosis Induced in Normal Mammary Epithelial Cells by a Novel Retinoid Cancer Res., April 1, 2000; 60(7): 2025 - 2032. [Abstract] [Full Text]
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M. J. Spinella and E. Dmitrovsky Aberrant Retinoid Signaling and Breast Cancer: the View From Outside the Nucleus J Natl Cancer Inst, March 15, 2000; 92(6): 438 - 440. [Full Text] [PDF]
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S. M. Lippman and R. Lotan Advances in the Development of Retinoids as Chemopreventive Agents J. Nutr., February 1, 2000; 130(2): 479 - 479. [Abstract] [Full Text]
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S. M. Lippman and P. H. Brown Tamoxifen Prevention of Breast Cancer: an Instance of the Fingerpost J Natl Cancer Inst, November 3, 1999; 91(21): 1809 - 1819. [Full Text] [PDF]
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J. Ayoub, R. Jean-Francois, Y. Cormier, D. Meyer, Y. Ying, P. Major, C. Desjardins, and W.E.C. Bradley Placebo-Controlled Trial of 13-cis-Retinoic Acid Activity on Retinoic Acid Receptor-Beta Expression in a Population at High Risk: Implications for Chemoprevention of Lung Cancer J. Clin. Oncol., November 1, 1999; 17(11): 3546 - 3552. [Abstract] [Full Text] [PDF]
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 S.-Y. Sun, H. Wan, P. Yue, W. K. Hong, and R. Lotan Evidence That Retinoic Acid Receptor beta Induction by Retinoids Is Important for Tumor Cell Growth Inhibition J. Biol. Chem., May 26, 2000; 275(22): 17149 - 17153. [Abstract] [Full Text] [PDF]
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