Autocrine metabolism of vitamin D in normal and malignant breast tissue.

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.

EXPERIMENTAL DESIGN:

Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D-activating enzyme 1alpha-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 1alpha-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.

RESULTS:

Expression of mRNA for 1alpha-hydroxylase (27-fold; P < 5 x 10(-11)), vitamin D receptor (7-fold; P < 1.5 x 10(-8)), and 24-hydroxylase (4-fold; P < 0.02) was higher in breast tumors. 1alpha-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.

CONCLUSION:

These data indicate that the vitamin D-activating enzyme 1alpha-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.

• Authors: Kelly Townsend, Claire M Banwell, Michelle Guy, Kay W Colston, Janine L Mansi, Paul M Stewart, Moray J Campbell, Martin Hewison
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 9 Pg. 3579-86 (May 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15867263 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligonucleotides, Antisense
• RNA, Messenger
• Receptors, Calcitriol
• Adenosine Triphosphate
• Cytochrome P-450 Enzyme System
• Steroid Hydroxylases
• Vitamin D3 24-Hydroxylase
• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
• Calcitriol
• Calcifediol

Topics

• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (genetics, metabolism)
• Adenosine Triphosphate (metabolism)
• Adult
• Aged
• Aged, 80 and over
• Breast (metabolism)
• Breast Neoplasms (genetics, metabolism, pathology)
• Calcifediol (metabolism, pharmacology)
• Calcitriol (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytochrome P-450 Enzyme System (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunohistochemistry
• Middle Aged
• Oligonucleotides, Antisense (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Receptors, Calcitriol (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Steroid Hydroxylases (genetics, metabolism)
• Vitamin D3 24-Hydroxylase