Nuclear vitamin D receptor expression is associated with improved survival in non-small cell lung cancer

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Abstract

Vitamin D has been shown to have anti-proliferative effects in a wide variety of cancers including lung cancer. The anticancer effects of vitamin D are mediated primarily by its active metabolite, 1,25-dihydroxyvitamin D (calcitriol), through vitamin D receptor (VDR) signaling. However, thus far there have been no studies evaluating the association between VDR expression and survival outcome in lung cancer. Using immunohistochemical analysis, we evaluated VDR expression, separately in the nucleus and cytoplasm, in lung cancer samples from 73 non-small cell lung carcinoma (NSCLC) patients with no prior therapy, and investigated the association between VDR expression and overall survival (OS). Cox proportional hazard models were used for our primary analyses. There were 44 deaths during a median follow-up of 51 months (range 13–93 months). High nuclear VDR expression was associated with improved OS after adjusting for age, gender, stage, smoking status, and histology (adjusted hazard ratio, 0.36; 95% confidence interval, 0.17–0.79). There was no association between cytoplasmic VDR expression and OS. Our results suggest that nuclear VDR status may be a prognostic marker in NSCLC. Future large studies to replicate our findings and to assess the impact of VDR gene polymorphisms on VDR expression are required as therapies targeting the vitamin D signaling pathway may be influenced by VDR status in the target lung cancer tissue.

Introduction

Vitamin D is a steroid hormone that has a well-documented role in calcium homeostasis and bone mineralization. Collective evidence from preclinical and epidemiological studies indicates that vitamin D status is also inversely associated with risk for various cancers and cancer mortality [1], [2]. Vitamin D is synthesized in the skin from 7-dehydrocholesterol through solar UV-B exposure or obtained through dietary sources and supplements, is metabolized in the liver to 25-hydroxyvitamin D (25(OH)D) and subsequently in the kidney into its active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol). Vitamin D and its analogues acting through genomic and non-genomic pathways inhibit cell proliferation, activate apoptotic pathways, inhibit angiogenesis, and exert pro-differentiative effects in a wide variety of cancers. The genomic pathway is mediated by vitamin D receptor (VDR), a 48 to 55 kD protein, and a member of the steroid hormone receptor super family present in various tissues, including lung. VDR is expressed by normal and neoplastic cell types, and is located primarily in the nucleus, although cytoplamic receptors have also been described. VDR is a ligand activated transcription factor. On binding with its ligand 1,25(OH)2D, VDR forms a heterodimer with the retinoid-X receptor (RXR), initiates transcription by interacting with a vitamin D response element (VDRE) in the promoter regions of target genes and modulates their expression [3], [4], [5], [6].

An inverse association between sunlight and colon cancer mortality was first described in 1980 by Garland & Garland who hypothesized that vitamin D protects against risk of colon cancer [7]. Subsequent epidemiological studies have shown an association between low circulating 25(OH)D levels, a biomarker of vitamin D exposure, and increased risk for colorectal, breast and prostate cancers [8], [9], [10]. An ecologic study showed an independent inverse association between UV-B radiation and vitamin D with reduced mortality at 15 cancer sites [11]. In lung cancer, circulating 25(OH)D levels, along with high vitamin D intake at the time of surgery, was associated with improved survival in early stage non-small cell lung carcinoma (NSCLC) patients [12], [13]. Polymorphisms in the VDR gene were also associated with improved survival in early stage NSCLC patients with squamous cell carcinoma in the same cohort [14]. The findings from these epidemiologic studies in lung cancer suggest that the integrity of the vitamin D signaling pathway plays a critical role in influencing outcome in NSCLC. Since the antitumor actions of vitamin D are mediated primarily through VDR [4], [5], knowledge of VDR status and its relationship to outcome is important in understanding the natural course of this disease. Additionally, therapeutic efforts targeting this pathway will be influenced by VDR status in the lung cancer tissue. With lung cancer continuing to remain the leading cause of cancer mortality worldwide despite progress in treatment and early detection, there is great interest in developing therapeutic options and preventative approaches for this disease using vitamin D and its analogues [15], [16].

VDR expression has been studied in cancers of the breast, colorectum, kidney, and lung [17], [18], [19], [20], [21], [22], [23]. VDR expression was associated with longer survival in human breast cancer [17], colorectal cancer [20], and cholangiocarcinoma [24]. However, there has been no study evaluating the association between VDR expression and survival outcome in lung cancer. Herein, we investigate the association of immunohistochemical expression of VDR with overall survival (OS) in a small cohort of patients with NSCLC. Our hypothesis was that VDR expression would be associated with improved overall survival. We assessed VDR expression in the nucleus and cytoplasm separately in order to evaluate the role of differential VDR expression.

Section snippets

Study participants and setting

The participants of this study belong to one of the cohorts recruited by the Tissue and Blood Bank Core and Biostatistics Core of the Specialized Program of Research Excellence (SPORE) in lung cancer at the University of Pittsburgh Cancer Institute, between July 1997 and January 2006, for translational research projects related to improving the diagnosis and prognosis of patients with NSCLC. It comprises patients with histologically confirmed diagnosis of NSCLC, ≥18 and ≤85 years of age, who

Patient characteristics

A majority of the 73 NSCLC patients were white (90%) and current or former smokers (96%), and two-thirds (66%) of the patients had early stage (stage IA–IIB) disease. Fifty-six percent of patients were female, and the median age of subjects in this study was 71 years (range 49–85). Adenocarcinoma and squamous cell carcinoma were the predominant histologies, 44% and 41% respectively (Table 1).

Of the 73 patients, 44 (60%) were deceased and 29 (40%) still alive at the time of last follow-up based

Discussion

We evaluated the association of VDR expression with OS in a small cohort of patients with NSCLC who had received no prior therapy. We found that high nuclear VDR expression was independently associated with better OS in the overall study population. No such association was observed for cytoplasmic VDR expression.

Our results support our hypothesis that VDR expression is associated with improved survival in NSCLC. The role of VDR signaling in mediating improved survival and preventing metastatic

Conclusion

In conclusion, the findings of our study, the first to evaluate the association of VDR expression with survival in NSCLC, although limited by sample size, show an independent association of nuclear VDR expression with better overall survival and suggest that analogous to estrogen receptor status in breast cancer, VDR may be a prognostic marker in NSCLC. Future large studies with more diverse racial groups to confirm the validity of our results, and to assess the impact of interaction of other

Acknowledgements

We thank Dr. Jane Cauley and Dr. Douglas Potter for insightful discussions; Ms Marie Acquafondata and Ms Marianne Notaro for technical assistance.

Funding source: This work was supported in part by the University of Pittsburgh Specialized Program of Research Excellence (SPORE) in Lung Cancer NCI P50 CA90440, and NIH RO1 CA132844 to P.A.H.

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