Research Papers:

Diet-derived 25-hydroxyvitamin D3 activates vitamin D receptor target gene expression and suppresses EGFR mutant non-small cell lung cancer growth in vitro and in vivo

Alissa R. Verone-Boyle _, Suzanne Shoemaker, Kristopher Attwood, Carl D. Morrison, Andrew J. Makowski, Sebastiano Battaglia and Pamela A. Hershberger

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:995-1013. https://doi.org/10.18632/oncotarget.6493

Metrics: PDF 3171 views  |   HTML 3354 views  |   ?  


Alissa R. Verone-Boyle1, Suzanne Shoemaker1, Kristopher Attwood2, Carl D. Morrison3, Andrew J. Makowski4, Sebastiano Battaglia1, Pamela A. Hershberger1

1Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

2Department of Bioinformatics & Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

3Department of Pathology and Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

4Heartland Assays LLC, Ames, IA 50010, USA

Correspondence to:

Alissa R. Verone-Boyle, e-mail: [email protected]

Pamela A. Hershberger, e-mail: [email protected]

Keywords: non-small cell lung cancer (NSCLC), EGFR, vitamin D, CYP27B1, zinc finger nucleases

Received: June 23, 2015     Accepted: November 15, 2015     Published: December 08, 2015


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6493