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Review
. 2017 Nov 4;18(11):2328.
doi: 10.3390/ijms18112328.

Vitamin D and VDR in Gynecological Cancers-A Systematic Review

Eileen Deuster  1 , Udo Jeschke  2 , Yao Ye  3 , Sven Mahner  4 , Bastian Czogalla  5
Affiliations
Review

Vitamin D and VDR in Gynecological Cancers-A Systematic Review

Eileen Deuster et al. Int J Mol Sci. .

Abstract

In recent years, a vast amount of studies have centered on the role of vitamin D in the pathogenesis of certain types of cancers such as breast, colorectal and lung cancer. Increasing evidence suggests that vitamin D and its receptor play a crucial role in the development of gynecological cancers. In this review, we systematically analyzed the effect of vitamin D and the vitamin D receptor on endometrial, ovarian, cervical, vulvar and vaginal cancer. Our literature research shows that vitamin D levels and vitamin-D-related pathways affect the risk of gynecological cancers. Numerous ecological studies give evidence on the inverse relationship between UVB exposure and gynecological cancer risk. However, epidemiologic research is still inconclusive for endometrial and ovarian cancer and insufficient for rarer types of gynecological cancers. The vitamin D receptor (VDR) is upregulated in all gynecological cancers, indicating its influence on cancer etiology. The VDR polymorphism FokI (rs2228570) seems to increase the risk of ovarian cancer. Other nuclear receptors, such as the RXR, also influence gynecological cancers. Although there is limited knowledge on the role of the VDR/RXR on the survival of endometrial, cervical, vulvar or vaginal cancer patients, some studies showed that both receptors influence survival. Therefore, we suggest that further studies should focus on the vitamin D- and its hetero dimer receptor RXR in gynecological cancers.

Keywords: VDR; cancer; cervical; endometrial; gynecological cancers; ovarian; vaginal; vitamin D; vitamin D receptor; vulvar.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The role of vitamin D and vitamin D receptor (VDR) in gynecological cancers: Endogenous synthesis of vitamin D begins with the oxidation of cholesterol, resulting in pro-vitamin D3. In the skin, ultraviolet B (UVB) radiation transforms pro-vitamin D3 to pre-vitamin D3. Pre-vitamin D3 isomerizes to vitamin D3, also named as cholecalciferol. Two hydroxylations by the enzymes vitamin D 25-hydroxylases (CYP27A1) and renal mitochondrial 1-hydroxylase (CYP27B1) are necessary to transform vitamin D3 into the active 1α,25(OH)2D3. Different tissues, as well as gynecological cancer tissue, can synthesize calcitriol. 1α,25(OH)2D3 binds to the vitamin D receptor which belongs to the family of nuclear receptors and forms a complex with retinoid X receptor (RXR) to regulate gene expression. Both vitamin D and its receptor have a protective role in gynecological cancers. Low levels of vitamin D are found in ovarian, cervical and vulvar cancer. As a response to cancer, the expression of the vitamin D receptor is upregulated in endometrial, ovarian, cervical and vulvar cancer.
Figure 2
Figure 2
VDR polymorphisms in ovarian cancer: The VDR gene spans 75 kb of DNA and is located on the chromosome 12q12-14, consisting of six 5′ noncoding exons (1a–1f) and eight coding exons (2–9). Several VDR polymorphisms have been identified: Fok1, Bsm1, Apa1, and Taq1. The restriction fragment polymorphism of Fok1 alters an ACG codon resulting in an additional start codon and thereby generating a longer VDR protein. The f allele indicates the absence of the restriction site encoding a 427–amino acid protein; the F allele shows the presence of the restriction site encoding a 424–amino acid protein. However, the longer version of the VDR protein exerts less transcriptional activity. Carrying the ff or Ff genotypes increase the risk of ovarian cancer.
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