Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model

Mazzilli, Sarah A.; Hershberger, Pamela A.; Reid, Mary E.; Bogner, Paul N.; Atwood, Kristopher; Trump, Donald L.; Johnson, Candace S.

doi:10.1158/1940-6207.capr-14-0403

Cited by 22 publications

(13 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and suggests that there might be increased nuclear translocation of VDR in MM. On the other hand, murine lung cancer studies have shown that nuclear VDR staining depends on VD sufficiency . Thus, it is possible to hypothesize that these differences between studies in nuclear staining in MM may reflect different VD status among populations living at different latitudes.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The anti-proliferative actions of 25D3 in vitro have been demonstrated in breast, pancreatic and prostate cancer cell lines [ 41 – 43 ]. In vivo , dietary vitamin D3 supplementation protects against cancer development [ 44 – 49 ] and inhibits outgrowth of human breast and prostate tumor xenografts [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Formalin-fixed, paraffin-embedded (FFPE) sections of human PMLs sampled from high-risk subjects undergoing screening for lung cancer were provided by RPCI as part of an IRB-approved study detailed below ( Supplementary Table S3). Dr. Candace Johnson at RPCI provided the FFPE lung sections from the Nnitroso-tris-chloroethylurea (NTCU) mouse model of lung SCC, from SWR/J mice treated with 25 mL of 40 mmol/L NTCU for 25 weeks in accordance with the Institutional Animal Care and Use Committee-approved protocol (41). Briefly, slides were deparaffinized and rehydrated.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression

Beane

Mazzilli

Tassinari

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Lung cancer is the leading cause of cancer-related death in the United States. The molecular events preceding the onset of disease are poorly understood, and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with lung cancer. Here, we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in lung cancer chemoprevention. Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with ( = 50) and without ( = 25) PMLs. Using surrogate variable and gene set enrichment analysis, we identified genes, pathways, and lung cancer-related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a chemoprevention-relevant biomarker. We identified 280 genes in the airway field associated with the presence of PMLs. Among the upregulated genes, oxidative phosphorylation was strongly enriched, and IHC and bioenergetics studies confirmed pathway findings in PMLs. The relationship between PMLs and squamous cell carcinomas (SCC) was also confirmed using published lung cancer datasets. The biomarker performed well predicting the presence of PMLs (AUC = 0.92, = 17), and changes in the biomarker score associated with progression/stability versus regression of PMLs (AUC = 0.75, = 51). Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high risk for PML progression and monitor outcome in chemoprevention trials. .

show abstract

Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model

Cited by 22 publications

References 49 publications

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

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

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

Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression

Contact Info

Product

Resources

About