vitamin D on Cancer and vice versa

Why proper levels of the storage vitamin D form as 25(OH)D3 are vitally important in cancer prevention.

The amount of research ongoing for vitamin D is mind-boggling. The fact that there exist synergistic actions between the 2 forms of vitamin D (passive D as 25-OHD3, and hormone D as 1,25(OH)2D3) opens up new avenues to determine the proper level for the passive storage form 25OHD3. It is known that the passive storage form 25OHD3 can turn into the active form right in some tissues with the help of a certain enzyme. The correct levels of 25OHD3 circulating in the body provides feedback mechanisms to produce the needed amount of this enzyme. And also provide enough for the Kidneys to produce the hormone form of D when reduced blood levels of calcium dictate. Since breast tissues are one place 25OHD3 is converted to the hormone D form to protect cells against becoming cancerous, let's start there to analyze what is happening.  

BREAST CANCER

Abstract - from PMID # 18767073

Mammary epithelial cell transformation is associated with deregulation of the vitamin D pathway.

Kemmis CM, Welsh J.

Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA.

"The vitamin D endocrine system mediates anti-proliferative and pro-differentiating signaling in multiple epithelial tissues, including mammary gland and breast tumors. The vitamin D metabolite 1alpha,25(OH)2D3 mediates growth inhibitory signaling via activation of the vitamin D receptor (VDR), a ligand dependent transcription factor. 1alpha,25(OH)2 D3 is synthesized from 25(OH)D3 (the major circulating form of the vitamin) by the mitochondrial enzyme CYP27b1 in renal and other tissues. Human mammary epithelial (HME) cells express VDR and CYP27b1 and undergo growth inhibition when exposed to physiological concentrations of 25(OH)D3, suggesting that autocrine or paracrine vitamin D signaling contributes to maintenance of differentiation and quiescence in the mammary epithelium. In the current studies we tested the hypothesis that cancer cells would exhibit reduced sensitivity to vitamin D mediated negative growth regulation. We used a series of progressively transformed HME cell lines expressing known oncogenic manipulations to study the effects of transformation per se on the vitamin D pathway. We report that mRNA and protein levels of VDR and CYP27b1 were reduced greater than 70% upon stable introduction of known oncogenes (SV40 T antigens and H-rasV12) into HME cells. Oncogenic transformation was also associated with reduced 1alpha,25(OH)2D3 synthesis, and cellular sensitivity to growth inhibition by 1alpha,25(OH)2D3 and 25(OH)D3 was decreased approximately 100-fold in transformed cells. These studies provide evidence that disruption of the vitamin D signaling pathway occurs early in the cancer development process."

   

Simple ANALYSIS

This discussion reveals that before cancer cells appear and grow into a tumor, vitamin D, as the passive D storage form 25(OH)D3, protects mammary cells by forming the hormone D form right in the cells and thus directs normal cell functions and cell division processes. But once cancer occurs or gets large enough to create problems, possibly due to low vitamin D levels, the damaged cells become transformed and start to de-activate these protective vitamin D actions. Here is how the cancer cells begin to upset the vitamin D protective mechanisms. First, the cancer cells actually increase the production of the hormone from of vitamin D. This devious move by cancer cells decreases the passive vitamin D levels which jeopardies future hormone D production abilities. At the same time, cancer cells also increase the speed that the hormone vitamin D form is de-activated and broken down into it's non-active metabolite form. Plus, cancer interferes with Vitamin D receptor (VDR) docking sites. These actions lower the protective abilities of the active vitamin D by 100 times compared to the levels observed in normal healthy breast tissue cells. 

This information gives scientists a couple of new enzyme avenues to attack in attempting to influence and control cancer cell growth rate, either by slowing the breakdown enzyme action, and/or increasing the enzyme necessary for the conversion into the hormone D form. 

Maintaining the proper level of the passive D form for long term prevention aspects sounds like the smartest option at this time, especially since the cancer cell essentially eliminates the vitamin D protective pathway as it grows larger.

Finding the proper 25OHD3 level is PRIORITY ONE.

The following research also supports this model:

Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

Kelly Townsend1, Claire M. Banwell1, Michelle Guy2, Kay W. Colston2, Janine L. Mansi2, Paul M. Stewart1, Moray J. Campbell1 and Martin Hewison1

 Authors' Affiliations:¹Division of Medical Sciences, Institute of Biomedical Research, Endocrinology and Metabolism, University of Birmingham, Birmingham, United Kingdom and ²Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, London, United Kingdom

Abstract

Purpose: Vitamin D seems to exert a protective effect against common cancers, although this does not correlate with circulating levels of active 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], indicating a more localized activation of vitamin D. The aim of this study was to investigate the significance of this in breast cancer. (It is the passive D levels and the amount of enzyme necessary to convert the passive D into the hormone D right in the cell that is of vital value)

Experimental Design: Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D–activating enzyme 1α-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41 tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1α-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.

Results: Expression of mRNA for 1α-hydroxylase (27-fold; P < 5 × 10⁻¹¹), vitamin D receptor (7-fold; P < 1.5 × 10⁻⁸), and 24-hydroxylase (4-fold; P < 0.02) was higher in breast tumors. 1α-Hydroxylase enzyme activity was also higher in tumors (44.3 ± 11.4 versus 12.4 ± 4.8 fmol/h/mg protein in nonneoplastic tissue; P < 0.05). However, production of inactive 1,24,25-trihydroxyvitamin D₃ was also significantly higher in tumors (84.8 ± 11.7 versus 33.6 ± 8.5 fmol/h/mg protein; P < 0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH)₂D₃. (this is the hormone D form)

Conclusion: These data indicate that the vitamin D–activating enzyme 1α-hydroxylase is up-regulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH)₂D₃ production in tumors by catalyzing catabolism to less active vitamin D metabolites. The enzymes involved in autocrine metabolism of vitamin D in breast tissue may therefore provide important targets for both the prevention and treatment of breast cancer."

WRAP UP

When Vitamin D levels as 25-OHD3 are within a proper range, they are able to enter into certain tissue cells such as breast, prostate, colon, pancreas, and with the help of an enzyme, produce the hormone D form with all it's cell protective activities.

Once cancer cells grow to a sufficient number, they develop mechanisms to defeat this vitamin D protective pathway by increasing the breakdown speed of the hormone D into a non-active form. This negates the protective affects of vitamin D by as much as 100 times.

NOTE: Looking at pancreatic cancer, a protective role of 30% reduction was found for individuals consuming about 600 IUs of vitamin D total compared to those consuming under 150 IUs. This might represent body levels of vitamin D at above 20 ng/ml as beneficial compared to less than 15 ng/ml. Plus, over 40 ng/ml offered no extra increased protection. Consuming the new mega dosages of 2500 IUs and up for over 3 months may not be wise as these amounts could build levels over 40. According to the NHANES chart and some research reports as mentioned in the Vitamin D facts article, this might not be wise for some conditions.