1 University Hospital Berne, Department of Medical Oncology, Bern 2 University of Bern, Department of Clinical Research, Bern 3 University of Bern, Institute of Pathology, Bern, Switzerland
* Correspondence to: Dr S. Aebi, Department of Medical Oncology, University Hospital Berne, Inselspital PT2C, 3010 Berne, Switzerland. Tel: +41-31-632-4114; Fax: +41-31-382-1237; Email: stefan.aebi{at}insel.ch
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Abstract |
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Patients and methods: The retinoid receptors comprise two classes, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each with three subclasses, , ß and
. We investigated the expression of the subtypes RAR
, RAR
, RXR
and RXRß by immunohistochemistry in ovarian cancers of 80 patients, and assessed their prognostic significance. In addition, we quantified the expression of retinoid receptor mRNA using real-time PCR and correlated the results with clinical characteristics.
Results: RAR and RXRß were highly expressed in a majority of ovarian cancers, particularly in advanced stages. High expression of RAR
was an independent negative prognostic factor of survival in addition to FIGO stage, age and p53 accumulation. The mRNA expression of retinoid receptors did not correlate with clinical properties of the tumors.
Conclusions: Retinoic acid receptors are frequently and strongly expressed in epithelial ovarian cancer and may be indicators of an adverse prognosis. This study provides the molecular basis for the therapeutic use of retinoids in ovarian cancer.
Key words: nuclear receptors, ovarian neoplasms, prognostic factors, retinoic acid receptors
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Introduction |
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Retinoids are potential candidates for new treatment strategies for ovarian cancer. Retinoids are natural and synthetic derivatives of retinol (vitamin A). The naturally occuring retinoids, all-trans retinoic acid, 9-cis retinoic acid and 13-cis retinoic acid, are generated from diet-derived retinol. Retinoids are ligands of cellular receptors of retinoic acid, including retinoic acid receptors (RARs) and retinoid X receptors (RXRs, rexinoid receptors) [4]. These are members of the steroid and thyroid hormone receptor superfamily [5
]. Each subtype of both retinoid receptor classes (RAR
, RARß, RAR
, and RXR
, RXRß, RXR
, respectively) is encoded by separate genes. Multiple isoforms of receptor subtypes exist as a result of alternate splicing. The receptors act mainly as RARRXR heterodimers, bind to specific DNA sequences (retinoic acid response elements) and act as ligand-dependent transcription factors [6
].
The physiological functions of retinoids include the control of proliferation, apoptosis and differentiation in normal cells during growth and development [6]. Retinoids are essential in the maintenance of normal adult epithelial differentiation. Vitamin A-deficient experimental animals have long been known to develop squamous metaplasia and other precancerous lesions. These alterations were reversed by vitamin A repletion [7
]. Several subsequent studies demonstrated the effect of retinoids in the chemoprevention of certain malignant tumors [1
, 8
, 9
]. Indeed, high dietary intake of carotenoids, which are precursors of the physiologic retinoids, had a moderate protective effect against ovarian cancer [10
14
]. The same effect was observed in a clinical trial evaluating the effect of the atypical retinoid fenretinide on the prevention of contralateral breast cancer [15
]. Surprisingly, none of the patients in the treatment group developed ovarian cancer during the intervention period. This benefit was lost when the drug was discontinued, suggesting an effect of fenretinide against ovarian cancer. [16
]. The growth inhibitory effect of retinoids has also been extensively studied in established ovarian carcinoma cell lines [17
]. Several in vitro studies revealed that numerous mechanisms are involved such as induction of apoptosis by various mechanisms [6
, 18
20
], interference with cell cycle control [21
] and cross-talk with other signaling molecules such as AP1 [22
] and epithelial growth factor [23
].
Retinoids enhance the effect of cytotoxic drugs, such as cisplatin [2426
] and docetaxel [27
], and of ionizing radiation [28
] in ovarian cancer cell lines. The toxic effects of retinoids differ from those of traditional cytotoxic agents. Thus, retinoids are potentially attractive partners for combination therapies with cytotoxic drugs. Certain retinoids are in clinical use, such as all-trans retinoic acid in the treatment of acute promyelocytic leukemia [29
] and targretin in the therapy of cutaneous T-cell lymphoma [30
], but their clinical application for the therapy of solid tumors such as ovarian cancer is still experimental.
Despite the knowledge of the biological effects of retinoids in ovarian cancer, limited information is available on the expression of retinoid receptors in these tumors [31]. Therefore, the aim of the present study was to determine the expression of RAR
, RAR
, RXR
and RXRß in paraffin-embedded ovarian cancer tissues using immunohistochemistry, and to measure the mRNA expression of all RAR and RXR subtypes in frozen tissue samples with real-time quantitative PCR.
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Patients and methods |
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Patient data
Patient information was collected from clinical records after obtaining the permission of the local ethics committee according to Swiss law; the patient information was immediately anonymized. All 80 patients included in the immunohistochemical study had undergone cytoreductive surgery. Patient ages ranged from 18 to 82 years (median 57.5). Forty-seven patients (59%) had serous carcinoma, 15 (18%) had mucinous carcinoma and 13 (16%) had endometrioid adenocarcinoma. Two patients (2%) were diagnosed with a clear cell carcinoma and three (4%) had unclassified carcinomas. Sixty-six of 80 patients had grade 2 or 3 carcinomas. The majority of the patients had FIGO stage III/IV disease at the time of diagnosis (40 of 80 stage III, 21 of 80 stage IV).
Patients included in the real-time PCR (RTPCR) analysis had undergone resection of a tumorous lesion of the ovary. Patient ages ranged from 41 to 83 years (median 61). Thirteen patients (37%) had ovarian adenomas and 22 (63%) had epithelial ovarian adenocarcinoma. Twenty-one of 22 carcinomas (96%) were grade 2 or 3. Seventeen of 22 patients had FIGO stage III/IV disease (10 stage III, seven stage IV). The main characteristics of both patient sets are summarized in Table 1.
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The monoclonal antibodies used included clone Vim3B4 for vimentin, DO-7 for p53, 124 for bcl-2, MIB-1 for Ki-67 (all from DakoCytomation), 336* for RARß, 147 for RXRß and 1373* for RXR (Neomarkers, Fremont, CA, USA); polyclonal antibodies were used for bax (DakoCytomation): RAR
, RARß*, RAR
, RXR
, RXRß* and RXR
* (all from Santa Cruz, CA, USA). Antibodies marked with an asterisk showed no reactivity when tested on various samples of formalin-fixed, paraffin-embedded tissues and were therefore not used for the study.
The expression of all antigens except p53, Ki-67 and bax was scored semiquantitatively by a modified histoscore method [34, 35
]. The proportion score (0,
5%; 1,
30%; 2,
50%; 3,
70%; 4,
95%; 5, >95%) was added to the intensity score (1, weak; 2, intermediate; 3, strong). Accumulation of abnormal p53 protein was defined as nuclear staining in >10% of tumor cells [36
]. For Ki-67, a proportion score was used (0, <5%; 1, <10%; 2, <40%; 3, >40%) [37
]. Bax was considered positive if the intensity score was 2 [38
]. Vimentin was used to assess the quality of the tissue sections [39
]. Each slide was evaluated independently by two observers (P.C.K. and M.K.); divergences were resolved using a double microscope.
cDNA synthesis and RTPCR
Thirty milligrams of frozen tumor tissue was disrupted with a mortar and pestle with concurrent cooling with liquid nitrogen. Total RNA was extracted using the RNeasy Mini kit (Qiagen, Basel, Switzerland) according to the manufacturer's instructions. cDNA was synthesized from 1 µg total RNA in 25 ml reaction buffer using MMLV reverse transcriptase, recombinant RNasin (Promega, Wallisellen, Switzerland) and random primers p(dN)6 (Roche, Rotkreuz, Switzerland) after DNase digestion with DNase I (Roche, Rotkreuz, Switzerland). The cDNA products were used for RTPCR in a reaction mixture (25 µl) containing 12.5 µl 2xSYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA, USA) and forward and reverse primer at 300 nM. The primers for RAR, RARß, RAR
and RXR
, RXRß, RXR
were designed according to the NCBI reference sequences for the corresponding genes (Table 2). 7S rRNA was used as reference target sequence (primers: 5'-accaccaggttgcctaagga and 5'-cacgggagttttgacctgct). We used the ABI PRISM 7700 Sequence Detection System for RTPCR. The following parameters were for used the RTPCR: initial denaturation (10 min at 95°C) followed by 45 amplification cycles (denaturation for 30 s at 95°C, annealing for 30 s at 55°C and elongation for 15 s at 72°C). We excluded the formation of primer dimers by final melting curve analysis after RTPCR (temperature slope 0.05°C/s from 40 to 100°C). All samples were measured as duplicates with a no-template control in each run. PCR products of each primer pair were cloned into plasmids using the TOPO TA Cloning Reaction (Invitrogen, Basel, Switzerland) and calibration curves for each resulting plasmid were established using 10-fold serial dilutions in 50 µg/µl yeast RNA (Ambion, Huntingdon, UK). The concentration of 7S was used as a control for RNA content and for normalization of RNA content of each sample.
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Results |
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The expression of RAR and RXR
was positively correlated (Spearman's rank correlation coefficient 0.32; P=0.004), as was that of RAR
and RXRß (correlation coefficient 0.26; P=0.02). RAR
was not correlated with the evaluated antigens. RXR
was also positively correlated with bax (correlation coefficient 0.22; P=0.04), as was RXRß with bcl-2 (correlation coefficient 0.27; P=0.014). No correlation was observed between markers of proliferation (Ki-67), p53 status and apoptosis (bcl-2 and bax).
Survival data are summarized in Figure 2 and Table 4. Patients with FIGO stage III and IV cancers had median survival times of 52 and 14 months, respectively, whereas the median survival was not reached in stage I and II cancers. RAR and RAR
were predictors of survival in univariate proportional hazards regression analysis, in addition to age, FIGO stage and p53 status. FIGO stage, p53 status and RAR
expression were independent predictors of survival: high expression of RAR
indicated a higher risk of death from ovarian cancer.
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Discussion |
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Despite substantial improvement of the surgical and medical therapy, ovarian cancer continues to be a highly lethal disease. Even with state-of-the-art surgery and modern chemotherapy, the probability of long-term survival is 30% for the majority of patients with stage III and IV disease [43
45
].
Retinoids have numerous biological effects: depending on the cellular context, they induce differentiation, inhibit the cellular proliferation or cause apoptosis [46]. All-trans retinoic acid was one of the first examples of targeted therapy: it induces remissions in a majority of patients with promyelocytic leukemia. Moreover, retinoids prevent the development of solid tumors [47
] including ovarian carcinoma [15
], and preliminary data indicate that retinoids are also effective in the therapy of certain solid tumors. In a recently reported phase II trial, fenretinide was shown to be active in ovarian cancer [48
]. Retinoids interact in vitro with conventional cytotoxic drugs such as cisplatin [24
26
] and the taxanes paclitaxel and docetaxel [27
, 49
, 50
] to lower the threshold of apoptosis. The clinical side-effects of retinoids do not overlap with the typical toxicity of cytotoxic chemotherapeutic agents. Thus, clinical and in vitro evidence make retinoids attractive investigational agents for the combination with conventional cytotoxic chemotherapy.
Most biological effects of retinoids are mediated through retinoid receptors; previous work has established that retinoid receptors are expressed in a variety of ovarian cancer cell lines. However, the expression of retinoid receptors has hardly been investigated in clinical ovarian cancer tissues. In the present study we observed that the retinoid receptors RAR, RAR
, RXR
and RXRß were present in a majority of ovarian cancer tissues, especially in advanced-stage tumors and those with poor differentiation. It is thus not surprising that the high expression of RAR
was a negative prognostic factor of survival. The lack of apparent correlation between the expression of mRNA and protein by immunohistochemistry may be explained by the impossibility of cross-calibration of antibody binding affinity and by the unavailability of a suitable antibody for RARß. Similar observations were made in oral squamous cell carcinoma, where RAR
was an independent indicator of a poor prognosis [51
]. RAR
was correlated with unfavorable prognostic factors such as high grade and high proliferation rate in prostate [52
] and breast [53
] cancer. Considering the role of retinoids in normal epithelial cell differentiation, the biological mechanisms underlying this observation are not obvious. At least two potential explanations have been proposed. (i) In human cell systems including MCF7 breast cancer cells, retinoic acid enhances the ubiquitylation of RAR
and induces its degradation in the proteasome [54
, 55
]. Thus, in conditions of low concentrations of retinoic acid at the receptor, the degradation of RAR
might be inhibited; alternatively, the post-transcriptional regulation of RAR
could be deranged by an unknown mechanism. (ii) Unliganded RAR
molecules may inhibit the retinoic acid-dependent processes such as differentiation [56
] and apoptosis, perhaps by inhibiting the effects of RARß; the expression of the latter is induced by liganded RAR
and is lost as an early event in the carcinogenesis of various tumors [57
].
The presence of RXRs, although not of independent prognostic value in this study, may also be important: RXRs are obligatory dimerization partners for other members of the steroid receptor superfamily such as other retinoid receptor subtypes, the thyroid hormone receptor, the peroxisome proliferator-activated receptor gamma (PPAR) and the vitamin D receptor. PPAR
has very recently been shown to be expressed in ovarian cancer and may play a role in the development of epithelial ovarian carcinoma [58
]. Thus, the expression of retinoic acid receptors may be a predictive marker for the therapeutic utility of retinoids and PPAR
ligands similar to the current use of estrogen receptor assessment for the prediction of endocrine responsiveness in breast cancer. Given the complexity of the retinoid signaling pathways it appears likely that retinoid receptors are required though not sufficient to predict the action of retinoids. For instance, the expression of RARß predicted the response to isotretinoin (13-cis retinoic acid) in a proportion of patients with renal cell cancer [59
]. Moreover, the RXR agonist bexarotene is active in about one-fifth of patients with metastatic breast cancer; unfortunately, it has not been investigated whether the expression of RXR is correlated with the responsiveness to bexarotene [60
]. In ovarian cancer, fenretinide induced a clinically worthwhile benefit in a minority of patients with ovarian cancer, even though the patients were not selected for retinoid receptor expression [48
]. It is conceivable that with a more selective use of retinoids exclusively in tumors that express retinoic acid receptors, a substantially better benefit to toxicity ratio may be achieved in combination with conventional chemotherapy.
Although the present investigation is limited by the small number of samples analyzed and the virtual lack of information on RARß protein, it reveals that certain retinoid receptors are present in human epithelial ovarian cancer. RAR may be associated with an adverse prognosis independently of established prognosticators such as FIGO stage. This finding will have to be verified in a larger independent set of tumor samples. The present study provides the molecular basis for clinical trials to evaluate the efficacy of retinoids in ovarian cancer; this prospect is promising in view of preclinical data that show a synergic interaction with platinum drugs and taxanes.
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Acknowledgements |
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Received for publication March 21, 2005. Revision received April 13, 2005. Accepted for publication April 14, 2005.
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