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 D 3 [1,25(OH) 2 D 3 ], 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 1a-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1a-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.Results: Expression of mRNA for 1a-hydroxylase (27-fold; P < 5 Â 10 À11), vitamin D receptor (7-fold; P < 1.5 Â 10 À8 ), and 24-hydroxylase (4-fold; P < 0.02) was higher in breast tumors. 1a-Hydroxylase enzyme activity was also higher in tumors (44.3 F 11.4 versus12.4 F 4.8 fmol/h/mg protein in nonneoplastic tissue; P < 0.05). However, production of inactive 1,24,25-trihydroxyvitamin D 3 was also significantly higher in tumors (84.8 F 11.7 versus 33.6 F 8.5fmol/h/mg protein; P < 0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH) 2 D 3 . Conclusion: These data indicate that the vitamin D^activating enzyme 1a-hydroxylase is upregulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH) 2 D 3 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.

25-Hydroxyvitamin D3 is a natural chemopreventive agent against carcinogen induced precancerous lesions in mouse mammary gland organ culture

“…To our knowledge, this is the first report to demonstrate 1α-hydroxylase expression in cultured normal and preneoplastic mouse mammary glands and enhanced expression in the presence of 25(OH)D 3 . It was reported that 1α-hydroxylase is expressed in both normal human breast tissue and breast cancer tissue, but the expression of 1α-hydroxylase in breast cancer tissue is either higher or similar to normal breast epithelial cells [24,30,31]. These results from human samples are in agreement with our observation in MMOC.…”

The vitamin D receptor in cancer

“…Supportively, levels of 25OH-D, the major circulating metabolite of vitamin D, are significantly lower in patients with breast cancer than in age-matched controls (114) . Furthermore, there are reduced CYP27b1 mRNA and protein levels in breast cancer cell lines and primary tumours (115) .…”

Toward a Core Nutraceutical Program for Cancer Management

“…288,289 Moreover, it is now clear that some, though not all, of the cancers that arise from these epithelia continue to express both 1α-hydroxylase and the vitamin D receptor; thus, it may be feasible to beneficially modify the behavior of these cancers through vitamin D supplementation. [281][282][283]290 There is certainly no doubt that calcitriol, or its less calcemic synthetic analogs, can suppress the growth and spread in nude mice of many human tumors that express the vitamin D receptor [291][292][293] ; such tumors, which likewise express 1α-hydroxylase activity, may be susceptible to supplemental vitamin D as well. Moreover, activated macrophages that infiltrate tumors may serve as a paracrine source of calcitriol when vitamin D is supplemented.…”