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25-hydroxyvitamin D...
25-hydroxyvitamin D3 1alpha-hydroxylase expression in breast cancer and use of non-hydroxylated vitamin D analogue
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- Segersten, Ulrika (författare)
- Uppsala universitet,Endokrinkirurgi
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Kaae Holm, Pernille (författare)
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- Björklund, Peyman (författare)
- Uppsala universitet,Endokrinkirurgi
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- Hessman, Ola (författare)
- Uppsala universitet,Endokrinkirurgi
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- Nordgren, Hans (författare)
- Uppsala universitet,Endokrinkirurgi
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Binderup, Lise (författare)
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- Åkerström, Göran (författare)
- Uppsala universitet,Endokrinkirurgi
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- Hellman, Per (författare)
- Uppsala universitet,Endokrinkirurgi
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- Westin, Gunnar (författare)
- Uppsala universitet,Endokrinkirurgi
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(creator_code:org_t)
- 2005-10-06
- 2005
- Engelska.
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 7, s. R980-R986
- Relaterad länk:
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https://uu.diva-port... (primary) (Raw object)
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https://breast-cance...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- INTRODUCTION:The cytochrome P450 mitochondrial enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase) of renal tubule cells hydroxylates the major circulating form of vitamin D (25(OH)D3) to the active systemic hormone 1,25(OH)2D3. Local production of 1,25(OH)2D3 appears to occur also at other sites where 1alpha-hydroxylase is expressed for autocrine/paracrine regulation. To reduce risks of hypercalcemia during treatment with vitamin D, we have previously suggested use of non-1alpha-hydroxylated vitamin D analogues to target tissues where 1alpha-hydroxylase is expressed, including the parathyroid glands in secondary hyperparathyroidism. The present study was undertaken to examine expression of 1alpha-hydroxylase in breast cancer and to investigate whether a non-1alpha-hydroxylated vitamin D analogue displayed biological function. In addition, expression of the 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) and the vitamin D receptor (VDR) was investigated.METHODS:The expression of 1alpha-hydroxylase, 24-hydroxylase and VDR was investigated in breast cancer specimens (n = 19) and normal breast tissues (n = 10) by immunohistochemistry and/or RT-PCR. Consecutive cryosections of 6 mum essentially free of immune cells were used in the analyses. The effect of vitamin D analogues on transcriptional activation was analyzed in transiently transfected MCF-7 breast cancer cells.RESULTS:1alpha-hydroxylase protein was demonstrated in 79% and 100% of breast cancer specimens and normal breast, respectively. The overall relative mRNA levels of 1alpha-hydroxylase and 24-hydroxylase in normal breast compared to breast tumors were: 1alpha-hydroxylase, 1 +/- 0.07 versus 0.7 +/- 0.05, respectively (p < 0.001); 24-hydroxylase, 1 +/- 0.08 verus 2.1 +/- 0.2, respectively (p < 0.001). The VDR was expressed in 95% of the tumors as expected, with mRNA levels of 1 +/- 0.09 and 1.4 +/- 0.12 (p < 0.05) in breast cancer and normal breast, respectively. The ketoconazole-sensitive transcription activation potential of the non-1alpha-hydroxylated vitamin D analogue prodrug of EB1089 (EB1285) was demonstrated in MCF-7 cells, which express 1alpha-hydroxylase. The activity of EB1285 was about 20% of 1,25(OH)2D3.CONCLUSION:These results demonstrate nearly normal expression levels of 1alpha-hydroxylase, 24-hydroxylase and VDR in the majority of investigated breast cancer specimens. A non-1alpha-hydroxylated vitamin D analogue displayed activity in breast cancer cells. Such analogues may present future therapeutic options for proliferative disorders where 1alpha-hydroxylase is expressed.
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