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Tumor Biology |
Allele in the Prostate Epithelium1
Departments of Biochemistry and Molecular Biology [J. H., T. M., H. M. S., P. R-B.], Pathology [W. C. P., A. C. K., J. W., P. R-B.], and Cell and Neurobiology [H. M. S.], Keck School of Medicine, University of Southern California, Los Angeles, California 90033; Center for Comparative Medicine, University of California-Davis, Davis, California 95616 [R. D. C.]; and Department of Pathology, The University of Iowa, Iowa City, Iowa 52242 [M. B. C.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(RXR) gene specifically in the prostatic epithelium of the mouse. Evidence for tissue-specific gene inactivation was obtained at DNA, RNA, and protein levels. Phenotypic changes in the prostate in the homozygous animals of different age groups ranging from 1 to 15 months were investigated. Developmentally, prostatic ductal branching appeared to be increased from the loss of RXR function. There was also a significant change in the profile of secretory proteins in the RXR mutant prostate relative to littermate controls with intact RXR allele. Histopathologically, homozygous RXR-deficient prostates showed multifocal hyperplasia as early as 4 months of age. Lesions, which could be described as low-grade prostatic intraepithelial neoplasias, were detected after 5 months. Subsequently, beginning at 
10 months, high-grade prostatic intraepithelial neoplasias developed in some animals. The incidences of low-grade prostatic intraepithelial neoplasias and high-grade prostatic intraepithelial neoplasias among the animals 10–15 months of age were 62 and 17%, respectively. The heterozygous mutant mice also developed similar prostatic phenotypes but in a delayed manner, implying a role of haploinsufficiency. Together, these results indicated for the first time that a major component of retinoid action in the prostate is mediated by a retinoid receptor, RXR, the inactivation of which in the prostatic epithelium leads to the development of preneoplastic lesions. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A role for vitamin A in prostate biology has long been appreciated (6) . For prostate development, offspring of vitamin A-deficient female mice exhibit squamous metaplasia or agenesis of the prostate (7) . Recent studies confirmed that exogenous RA can significantly inhibit ductal growth and branching of AP, DP, LP, and VP in mice (8 , 9) . In regard to carcinogenesis, prostate carcinoma tissues contain significantly less endogenous retinoids and its biologically active metabolite, RA, than normal prostate (10) . Epidemiological studies also revealed an inverse trend between serum vitamin A levels and subsequent incidence of prostate cancer (11 , 12) . Furthermore, retinoids, as differentiation agents, have attracted much interest for prostate cancer prevention and treatment. There is evidence that retinoids could effectively inhibit tumor growth and progression in various chemical-induced mouse prostate cancer models (13, 14, 15) . In studies with human prostate cancer cell lines, retinoids alone or with other chemotherapeutic agents reduced their clonal growth and tumorigenic potential (16 , 17) . Although clinical trials with retinoids for prostate cancer indicated only limited efficacy to date, it is, however, contended that improved pharmacokinetics and application of selective retinoid analogues might lead to a better clinical outcome (18, 19, 20, 21) .
Actions of retinoids are mediated either by its nuclear receptors or through receptor-independent mechanisms. There are two families of RA receptors, RARs (, ß, and 
) and RXRs (, ß, and ; Refs. 22
, 23
). The physiological consequences of RAR and RXR inactivation were investigated via conventional knockout technology. It was reported that RAR null mutant mice developed squamous metaplasia of the prostate (24)
. Because mice lacking both RXRß and RXR were normal in terms of prostate morphology and function (25)
and considering that the active RA receptor is indeed a heterodimer of one RAR and one RXR (26)
, the critical RXR in prostate biology appears to be RXR. Moreover, to mediate multiple signaling pathways in the prostate, RXR may partner with other nuclear receptors, such as PPAR and vitamin D receptor, the ligands of which have been shown to inhibit prostatic cancer cell growth (26
, 27)
.
Because conventional disruption of the RXR gene is embryonic lethal (28
, 29)
, we used our PB-Cre4 mice (30)
, which express a high level of Cre recombinase specifically in the prostatic epithelium, to breed with floxed RXR mice (31)
to selectively mutate the RXR gene for a direct assessment of the role of RXR in the prostate. We document here that RXR is a critical gene function in maintaining normal phenotype of the gland because loss of RXR function results in developmental and functional abnormalities as well as preneoplastic lesions in the prostate.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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mice (31)
were described previously. PB-Cre4 male mice were crossed with RXRfloxed/floxed female mice to abolish RXR function in the prostatic epithelium. Experimental male animals carried one allele of PB-Cre transgene and were either homozygous for the floxed RXR allele (RXRfloxed/floxed) or heterozygous carrying one wild-type and one floxed allele (RXRwt/floxed). Because the floxed RXR allele is functionally identical to the wild-type allele, control male animals used were either RXRwt/floxed or RXRfloxed/floxed or RXRwt/wt and did not carry the Cre transgene.
PCR and RT-PCR Analysis.
Genomic DNA was extracted from mouse tissues by digestion with 20 µg/ml proteinase K (Life Technologies, Inc., Buffalo, NY) at 50°C for overnight. Aliquots (0.5 µg) of genomic DNA were used for the PCR analysis. Primers for RXR amplification were 5'-ACCAAGCACATCTGTGCTATCT-3' and 5'-ATGAAACTGCAAGTGGCCTTGA-3'. PCR products were approximately 1.5 kb, 1.7 kb, and 500 bp, corresponding to wild-type, floxed, and floxed-out RXR allele, respectively. For RT-PCR, total RNA was extracted from the tissue samples using RNeasy Mini kit (Qiagen, Valencia, CA). Total RNA was converted to cDNA by random priming and then amplified for 32 cycles using primers 5'-TGCCCATCCCTCAGGAAATATGG-3' and 5'-TGTTTGCCTCCACGTATGTCTC-3'.
Quantitative RT-PCR.
Total RNA was extracted from individual prostatic lobes by guanidinium isothiocyanate extraction procedure. Quantitative RT-PCR was performed as described by Makita et al. (32)
. Briefly, PCR reactions including [32P]dCTP were first run with 18S RNA primers and competimers to normalize for input between samples; subsequent reactions for retinoid receptor transcripts were done under conditions where amplification was in the linear range. PCR products were separated by acrylamide gel electrophoresis, dried, and exposed to film and also analyzed quantitatively by PhosphorImaging (Amersham Pharmacia Biotechology, Piscataway, NJ). The sequences of the primers used in this study were: RXRß, 5'-GCTCATTGGCGACACCCCCA-3' and 5'-GAAGGTAGACATAAAGTCCT-3'; and RXR, 5'-ACGGGCCATCGTGCTGTTTAAC-3' and 5'-CAGCTGAGGAGGTTCAGGTG-3'. The primers used for RAR and RARß were reported previously (33)
. The primers for RAR were as described (34)
.
Immunohistochemistry.
Zymed BrdUrd staining kit (Zymed, South San Francisco, CA) was used for BrdUrd staining. Briefly, sections were incubated with biotinylated anti-BrdUrd antibody and detected by the streptavidin-peroxidase with diaminobenzidine as a chromogen. Slides were then counterstained with methylene green (KPL Labs, Gaithersburg, MD). RXR immunostaining using a rabbit polyclonal antibody against the NH2 terminus of RXR (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was performed in a similar way except for antigen retrieval by microwave heating in 1 M urea. Tissue sections, which were not incubated with primary antibody, served as negative controls.
Tissue Preparation.
A 150-µl solution of 10 mg/ml BrdUrd (Sigma Chemical Co., St. Louis, MO) was injected i.p. 1 h before animals were sacrificed. The urogenital system was surgically isolated, and the individual prostatic lobes were dissected out under a dissecting microscope. Tissues for histopathological observation were fixed in 10% neutral buffered formalin (Surgipath, Richmond, IL) for overnight. Fixed tissues were processed and embedded in paraffin. Thin sections (5 µm) were produced and stained with H&E. Tissues for RNA assays were frozen in liquid nitrogen immediately after dissections until usage.
Phenotypic Analysis of RXR Mutant Prostates.
Experimental male mice ranging in age from 1 to 15 months for homozygous RXR deletion or up to 18 months of age for the heterozygous allele were examined. For analysis of secretory proteins, individual lobes of the dissected prostates were collected in PBS containing a protease inhibitor mixture (Roche Diagnostics Corp., Indianapolis, IN), punched with a 28-gauge needle, and then centrifuged (3)
. Secretory proteins in the supernatant fluids were resolved on 10–20% SDS-polyacrylamide gels (Bio-Rad Laboratories, Hercules, CA). Coomassie blue staining was used for visualization.
For branching analysis, microdissection of LP, DP, VP, and AP was performed as described previously using collagenase to facilitate the process (3)
. The number of branch tips was quantitated by examination of the photographed specimen. A statistical analysis (ANOVA) was performed to determine the difference in branching morphogenesis between wild-type and RXR-deficient prostates.
For analysis of histopathology, 16 control animals ranging from 1 to 18 months, which showed normal histology, along with 45 homozygous and 16 heterozygous RXR-mutant mice were sacrificed and analyzed. A grading system for PIN-like lesions was used to evaluate RXR-deficient animals. Generally, PIN lesions were categorized into LGPIN and HGPIN based on their architecture, differentiation pattern, and degree of cytological atypia. LGPINs showed mild cytological atypia. HGPINs were distinguished from LGPINs by the advanced degree of epithelial cell proliferation, nuclear stratification, and cytological atypia.
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RESULTS |
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-deficient Prostates. allele had two loxP sites introduced into the introns surrounding the fourth exon of the gene, an exon that encodes an essential domain of the RXR protein (31)
. When the intervening sequence (including the fourth exon) is deleted, the gene is converted into a loss-of-function allele. Before initiating breeding experiments for conditional inactivation of the RXR allele in the prostate, we examined RXR expression in the prostate of the normal mice with the RXR conditional alleles by immunohistochemistry. The results, as illustrated in Fig. 1C
, revealed that RXR expression could be readily detected in the prostatic epithelium. It was, therefore, considered highly appropriate to cross the floxed RXR mice with our PB-Cre4 mouse line (30)
, which expresses Cre recombinase with high specificity and penetrance in the prostatic epithelium. We crossed PB-Cre4 male mice with floxed RXR female mice to recover both Cre+/-RXRwt/floxed and Cre+/-RXRfloxed/floxed male mice for the following phenotypic studies in the prostate.
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Gene Disruption in Prostate Epithelial Cells. gene under the direction of the PB-Cre transgene, genomic DNA was isolated from various tissues of Cre+/-RXRwt/floxed male mice and analyzed by PCR amplification. At 3 months, recombination of the conditional RXR allele was prominent in VP, LP, and DP but significantly lesser in AP. No tissues other than prostate displayed strong recombination, except that epididymis, seminal vesicle, and ductus deferens showed low levels of recombination (30)
. However, in mice 14 months of age, prominent recombination had occurred in all prostatic lobes (Fig. 1A)
. To further demonstrate the effectiveness of Cre-mediated recombination of the RXR gene, we isolated RNA from prostatic tissues of Cre+/-RXRfloxed/floxed mice 3 months of age and evaluated it by RT-PCR. A deleted but stable transcript was detected in DP, LP, VP, and AP, indicating efficiency and specificity of our Cre-loxP system for RXR inactivation (Fig. 1B)
. Considering the potential that a dominant-negative RXR protein might be produced from deleted transcripts, we used immunohistochemistry technique to explore expression of RXR using antibodies against a domain contained in both normal and the putative mutant RXR protein. No detectable level of RXR expression was observed in the RXR mutant prostate compared with strong signals detected in the control prostate (Fig. 1C)
. It appeared that if the truncated transcript was translated, the protein product lacked stability.
Lack of Compensatory Increase in Other Retinoid Receptors in RXR-deficient Prostates.
In several mouse gene knockout models, mutation of one gene can result in compensatory expression by other members of the same gene family. To determine whether this occurs in the prostate of our hybrid model, LP tissues from RXRfloxed/floxed mice 3 months of age, either bearing the PB-Cre transgene or not, were isolated to extract RNA and analyzed by quantitative RT-PCR. As shown in Fig. 2
, other five members of retinoid receptors were expressed in the prostate, and expression of other retinoid receptor genes was not significantly changed as a consequence of RXR gene inactivation, indicating a lack of compensatory up-regulation of RARs and other RXRs. Therefore, phenotypic changes in RXR-deficient prostates, described below, were primarily attributable to RXR inactivation rather than changes in expression of other retinoid receptors, at least at the level of transcripts.
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Inactivation Results in Increased Branching Morphogenesis in the Prostate.wt/floxed and Cre+/-RXRfloxed/floxed male mice were born and reared normally without exterior abnormalities up to 18 months of age, the point of maturity of this report. We first addressed the effect of RXR inactivation in prostate development. In mice, development of the prostate is induced in late gestation when the epithelium of urogenital sinus grows into the surrounding mesenchyme to form prostate ductal buds. Subsequent branching morphogenesis of ductal systems occurs largely in the postnatal period by a process of concentrated mitotic activity at ductal tips, lumenalization of epithelial extensions, and branching of ducts (8)
. The mechanisms regulating the branching process remain unknown. Because the probasin promoter that we used to drive Cre expression only becomes active after birth, we circumvented the confounding effects of possible prostatic bud abnormalities on branching morphogenesis (30
, 35)
. Gross inspection of RXR mutant prostate glands did not reveal any noteworthy abnormalities. RXR-deficient and RXR-intact prostates did not appear to differ in size or weight to any significant extent. LP, DP, VP, and AP were microdissected to assess their branching patterns quantitatively by counting the number of distal ductal tips. In the RXR conditional knockout group, all lobes appeared to show increased branching morphogenesis, as shown in Fig. 3
. In LP and AP, there was a 54 and 52% increase in the number of ductal tips, respectively. For DP and VP, changes were less pronounced (Fig. 4)
. Several reports suggested involvement of RA in the prostate ductal morphogenesis, possibly by receptor-mediated effects on Hox gene clusters, which are known to control morphogenesis in a variety of systems (9
, 36)
. Although it is difficult to address effects of RXR inactivation on prostatic bud formation in our mouse model, our results suggested that RA action, at least on the prostate branching process, is mediated through RXR.
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Deficiency Altered Secretory Protein Profiles in the Prostate.floxed/floxed and control Cre-/-RXRfloxed/floxed animals 6 months of age and then resolved the secretions on SDS-PAGE gel. Reproducible changes of protein profiles were detected in LP, DP, and VP without significant changes in AP (Fig. 5)
. RXR deletion caused both decreases and increases in major secretory proteins. Those results suggested that RXR, as a transcription factor, played both positive and negative regulatory roles in prostatic gene expression. Although identities of those altered protein bands remained unknown, this finding underscored a potential role for RXR-mediated transcription control in normal prostatic function, specifically in relation to protein secretions. However, because all conditional male animals examined to date are fertile, the significance of those changes could not be attributed to biological reproductive function.
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Mutant Prostate. mutant prostate was hyperplasia, which, with advancing age, was accompanied by PIN lesions. Homozygous RXR inactivation in mice older than 4 months demonstrated multifocal areas of epithelial hyperplasia with an incidence rate of 71%. Lesions became more severe and progressed to LGPINs after 5 months of age. As shown in Fig. 6, A and B
, prostate glands showed abnormal configuration with nuclear stratification. Although there were abundant cytoplasms, nuclear sizes were enlarged with prominent nucleoli indicating malignant nature. Interestingly, focal areas of LGPINs were detected at multiple sites in the same animal, suggesting continuity in the progression of those lesions. After 10 months of age, HGPINs were detected in some animals. In Fig. 6, C and D
, areas of normal morphology with a single-cell layer of secretory epithelium, together with areas of LGPINs and HGPINs, were clearly illustrated. In HGPINs, cells with sparse cytoplasm almost filled the lumen of prostate glands, and the nucleus showed hyperchromatism, pleomorphism, and prominent nucleoi. Along with aging, the incidence of LGPINs and HGPINs increased to 62 and 17%, respectively, at age groups from 10 to 15 months, which represented the oldest animals examined to date for homozygous RXR mutant mice (Fig. 7A)
. For heterozygous RXR-deficient mice, hyperplasia and LGPINs were demonstrated starting at the age of 11 and 14 months, respectively. HGPINs occurred after 18 months (Fig. 7B)
. In an example shown in Fig. 6E
, lesions demonstrated different nuclear characteristics compared with normal prostatic epithelial cells: dense nucleus and prominent nucleoi. Moreover, three mitotic figures were prominent, including one abnormal tripolar mitotic figure in the field. These data supported the notion that RXR might be involved in preventing initiation of abnormalities in the prostatic epithelium.
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. For this purpose, we used the procedure of short-term exposure to BrdUrd in vivo followed by immunohistochemical detection of cells with BrdUrd incorporation. In control mice, all lobes were mostly unlabelled, with rare incorporation into scattered epithelial cells. In contrast, in the RXR-deficient prostate, there was a pronounced increase in the percentage of labeled nuclei as shown in Fig. 6F
. Thus, a normal function of RXR appeared to be to maintain growth regulation in prostatic epithelium, and loss of RXR resulted in an elevated proliferation rate, and presumably as a consequence, led to PINs. |
DISCUSSION |
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gene is mapped, is characterized by a high rate of recombination (42)
, and the incidence of loss of heterozygosity at this locus has been reported to be 20% in prostate cancer (43)
. Although absence of or loss of expression of RARß is a common phenomenon in several types of cancer including prostate cancer (44, 45, 46)
, RXR expression in prostate cancer remains largely unknown, and its investigation is further complicated by the recent finding that phosphorylation of RXR can abolish its transactivation activity (47)
.
The investigations presented here address the role of loss of activity of RXR specifically in the epithelium of the mouse prostate. The development of the PB-Cre4 transgenic mouse line with a robust and tissue-specific expression of Cre recombinase (30)
allowed us to circumvent the embryonic lethality that is caused by conventional knockout of the RXR gene in the mouse (28
, 29)
. Our data from the Cre-loxP model that we developed demonstrate that the presence of RXR is required for the normal control of prostate growth and differentiation. In its absence, i.e., in the homozygous mutant animals, a substantial increase in ductal branching is induced in the prostate, most notably in the lateral and anterior lobes. Besides this aberrant ductal morphogenesis, there are a few other pronounced effects that could be directly attributed to loss of RXR function in the prostatic epithelium. Evidence is also presented to support that there is no compensatory changes in the expression of any of the other RXR or RAR receptor family members in the prostate of these animals.
A deficiency in RXR is sufficient to drive proliferation in the prostatic epithelium to produce multifocal hyperplasia as early as 4 months of age. Hyperplasia appears to precede the development of histopathologically identifiable lesions, many of which resemble human preneoplastic prostatic lesions. A stochastic pattern of increased degree of phenotypic abnormalities of lesions, beginning with epithelial hyperplasia followed by presentations of LGPINs and then by HGPINs is noted. For example, the incidence of hyperplasia, which is 63% during 1–9 months, increases to 76% by 10–15 months. The frequency of detection of LGPIN is only 19% at 1–9 months to increase to 62% at 10–15 months. Similarly, HGPIN, not detected up to 9 months, becomes 17% by 15 months. The development of progressive lesions is likely to be a multistep process that requires cumulative changes in gene expression. Thus, it seems that loss of RXR function may make some of the affected cells escape negative growth control mechanisms, leading to hyperplasia. Increased proliferation is likely to enhance the probability to acquire additional genetic alterations to produce a higher degree of dysplasia. At this time, we have no direct evidence to support that LGPIN actually progresses to HGPIN, or even whether specific defined areas of hyperplasia turn to LGPIN, although detection of PINs, in general, is always associated with hyperplasia, as HGPINs with LGPINs but not vice versa. The lesions, however, do not progress to frank adenocarcinoma, at least during the 15 months of observation. This is not surprising because other genetic events necessary for progression from preneoplastic lesions to neoplasia may manifest only with further aging, a point that remains to be determined.
We also document reproducible changes in secretory protein profiles in the prostatic lobes, mainly LP, DP, and VP, attributable to RXR gene inactivation, although the nature of the secreted proteins remains to be identified. Because some proteins are up-regulated and others are down-regulated, their characterization should be valuable in deriving clues for both positive and negative aspects of RXR-mediated transcription control in the prostatic epithelium. In this regard, it is noteworthy that the prostatic spermine-binding protein, which is normally a major secretory protein in VP, is actually lost in the Nkx3.1 mutant mice.
While studying biallelic inactivation of RXR gene, we also accumulated animals with monoallelic deletion. Similar to homozygous mice, the monoallelic mice appear to develop hyperplasia, LGPIN, and HGPIN in a temporal fashion, except that the incidence is substantially delayed by several months. Haploinsufficiency at several gene loci, such as Nkx3.1 (3
, 48)
and p27 (49)
, leading to a dosage defect, has been observed in prostate tumorigenesis. We suggest that the RXR protein is such a gene product, the reduced production and delayed accumulation of which might promote a positive environment for proliferation and transformation to preneoplastic lesions in the prostate. In this regard, a scrutiny of not only loss of heterozygosity at the RXR gene locus but also of mutations of one or both RXR alleles in human prostate cancer might be worthwhile.
Because RXR is an obligatory heterodimeric partner for RARs, vitamin D receptor, PPAR, thyroid hormone receptor, and some other nuclear receptors, it could be considered as a pivotal coordinating molecule in multiple signaling pathways. Retinoids, PPAR-specific ligands, and vitamin D analogues have been shown to inhibit prostate cancer cell proliferation and clonal growth (16
, 17
, 27
, 50, 51, 52)
. Retinoids are also the most investigated class of chemopreventive agents, and some promising results have been obtained on their utility in certain rodent models for prostate cancer (53
, 54)
. Considering these issues, it seems that future studies on changes in gene expression in the prostatic epithelial cells of RXR-inactivated mouse should help to elucidate the negative regulatory role of RXR in normal prostatic epithelium and in the development of prostatic preneoplastic lesions. Additionally, our results point to the potential value of testing RXR-specific ligands in attempts to prevent development of prostate cancer.
In summary, our results demonstrate a functional role of RXR in various aspects of prostate biology, including control of ductal branching, protein secretions, proliferation of epithelial cells, and then progression to premalignant phenotypes. The conditional RXR mutant mice produced should be a valuable resource to examine RXR signaling mechanisms in relation to the prostate, because they might be useful in studies of therapeutic regimens or chemoprevention of the beginning stages of prostate tumorigenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This research was supported by NIH Grant R01 CA 59705 and, in part, by a grant from the T. J. Martell Foundation, NIH Grant R21 DK 59192, and NIH Predoctoral Training Grant Fellowship T32 CA 09569 (to A. C. K.). 
2 To whom requests for reprints should be addressed, at Department of Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033. Phone: (323) 442-1184; Fax: (323) 442-3049; E-mail: royburma{at}usc.edu
3 The abbreviations used are: PIN, prostatic intraepithelial neoplasia; LGPIN, low-grade PIN; HGPIN, high-grade PIN; RA, retinoic acid; RAR, RA receptor; RXR, retinoid X receptor; AP, anterior prostate; DP, dorsal prostate; LP, lateral prostate; VP, ventral prostate; PPAR, peroxisome proliferator-activated receptor ; RT-PCR, reverse transcription-PCR; BrdUrd, bromodeoxyuridine.
Received 3/29/02. Accepted 6/14/02.
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REFERENCES |
|---|
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, and paclitaxel in patients with prostate cancer and other advanced malignancies. J. Clin. Oncol., 17: 2213-2218, 1999. in the mouse. Cell, 73: 643-658, 1993.[Medline]
null mice are apparently normal and compound RXR +/-/RXRß -/-/RXR -/- mutant mice are viable. Proc. Natl. Acad. Sci. USA, 93: 9010-9014, 1996. (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res., 58: 3344-3352, 1998. developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell, 78: 987-1003, 1994.[Medline]
mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev., 8: 1007-1018, 1994. gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development (Camb.), 125: 1943-1949, 1998.[Abstract]
. Genes Dev., 14: 464-474, 2000. with a novel putative transcription factor, PML. Cell, 66: 663-674, 1991.[Medline]
at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. Cancer Res., 61: 7675-7682, 2001.This article has been cited by other articles:
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|
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|
|
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 X.-H. Tang, M.-J. Suh, R. Li, and L. J. Gudas Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid J. Lipid Res., January 1, 2007; 48(1): 165 - 176. [Abstract] [Full Text] [PDF]
|
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|
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|
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|
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|
|
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|
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|
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