Diet-derived 25-hydroxyvitamin D3 activates vitamin D receptor target gene expression and suppressesEGFRmutant non-small cell lung cancer growthin vitroandin vivo

Abstract

Epidemiologic studies implicate vitamin D status as a factor that influences growth of EGFR mutant lung cancers. However, laboratory based evidence of the biological effect of vitamin D in this disease is lacking. To fill this knowledge gap, we determined vitamin D receptor (VDR) expression in human lung tumors using a tissue microarray constructed of lung cancer cases from never-smokers (where EGFR gene mutations are prevalent). Nuclear VDR was detected in 19/19 EGFR mutant tumors. Expression tended to be higher in tumors with EGFR exon 19 deletions than those with EGFR L858R mutations. To study anti-proliferative activity and signaling, EGFR mutant lung cancer cells were treated with the circulating metabolite of vitamin D, 25-hydroxyvitamin D3 (25D3). 25D3 inhibited clonogenic growth in a dose-dependent manner. CYP27B1 encodes the 1α-hydroxylase (1αOHase) that converts 25D3 to the active metabolite, 1,25-dihydroxyvitamin D3 (1,25D3). Studies employing VDR siRNA, CYP27B1 zinc finger nucleases, and pharmacologic inhibitors of the vitamin D pathway indicate that 25D3 regulates gene expression in a VDR-dependent manner but does not strictly require 1αOHase-mediated conversion of 25D3 to 1,25D3. To determine the effects of modulating serum 25D3 levels on growth of EGFR mutant lung tumor xenografts, mice were fed diets containing 100 or 10,000 IU vitamin D3/kg. High dietary vitamin D3 intake resulted in elevated serum 25D3 and significant inhibition of tumor growth. No toxic effects of supplementation were observed. These results identify EGFR mutant lung cancer as a vitamin D-responsive disease and diet-derived 25D3 as a direct VDR agonist and therapeutic agent.

Immunohistochemical expression of vitamin D receptor in melanocytic naevi and cutaneous melanoma: a case-control study

“…In vitro studies in breast cancer, colon cancer and lung cancer have shown that those cell lines that express VDR respond to VD supplementation with an anticarcinogenic effect. [22][23][24] Our study has some limitations. The small sample size of the study patients and the small number of patients with invasive, thick and metastatic MM might have influenced the lack of association between prognostic factors and VDR status, and no definite statements can be made in this subgroup of melanomas.…”

“…As in other neoplasms, tissue VDR status may suggest which patients with MM might be candidates for VD supplementation as an adjuvant treatment. In vitro studies in breast cancer, colon cancer and lung cancer have shown that those cell lines that express VDR respond to VD supplementation with an anticarcinogenic effect …”

Vitamin D Receptor Signaling and Cancer

“…148 Numerous studies have examined the ability of dietary or pharmacologic addition of vitamin D compounds to either prevent tumor formation or inhibit the growth of xenograft tumors. 82,[149][150][151][152][153][154][155][156][157][158][159] One area of investigation is the impact of experimental dietary variations and their impact on tumor predisposition. Long-term studies of mice fed with a Western-style diet (eg, high fat and phosphate and low vitamin D and calcium content) have been exploited to examine the impact of vitamin D on colon cancer proliferation.…”

Vitamin D-Related Gene Polymorphisms, Plasma 25-Hydroxy-Vitamin D, Cigarette Smoke and Non-Small Cell Lung Cancer (NSCLC) Risk

“…Moreover, as a subgroup, they have been widely analyzed in multitudinous cancer-related studies [15,16]. However, in previously conducted studies, genetic variation in VDR has not been systematically analyzed with regard to NSCLC, and very limited data are available on CYP27B1 and CYP24A1 polymorphisms [17,18]. In addition, epidemiological and clinical studies inspecting the associations between NSCLC risk and vitamin D status are limited in number and inconclusive [19,20].…”