Tumoral Vitamin D Synthesis by CYP27B1 1-α-Hydroxylase Delays Mammary Tumor Progression in the PyMT-MMTV Mouse Model and Its Action Involves NF-κB Modulation
| Autor: | Anne Camirand, Jiarong Li, René St-Arnaud, Ibtihal Fadhil, Richard Kremer, William Muller, Benoît Ochietti, Timothy A. Reinhardt, Aimée-Lee Luco |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Angiogenesis Prohormone Apoptosis Mammary Neoplasms Animal In Vitro Techniques Biology Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Breast cancer Calcitriol Mammary tumor virus Internal medicine Tumor Cells Cultured medicine Vitamin D and neurology Animals Vitamin D Calcifediol Cell Proliferation 25-Hydroxyvitamin D3 1-alpha-Hydroxylase Mammary tumor Cell growth NF-kappa B medicine.disease Immunohistochemistry Mice Mutant Strains Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Disease Progression Calcium Female Signal Transduction medicine.drug |
| Zdroj: | Endocrinology. 157:2204-2216 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2015-1824 |
| Popis: | Biologically active vitamin D (1,25-dihydroxycholecalciferol or 1,25(OH)2D) is synthetized from inactive prohormone 25-hydroxycholecalciferol (25(OH)D) by the enzyme CYP27B1 1-α-hydroxylase in kidney and several extrarenal tissues including breast. Although the development of breast cancer has been linked to inadequate vitamin D status, the importance of bioactive vitamin D production within tumors themselves is not fully understood. To investigate the role of tumoral vitamin D production in mammary epithelial cell progression to breast cancer, we conducted a Cre-loxP-mediated Cyp27b1 gene ablation in the mammary epithelium of the polyoma middle T antigen-mouse mammary tumor virus (PyMT-MMTV) mouse breast cancer model. Targeted ablation of Cyp27b1 was accompanied by significant acceleration in initiation of spontaneous mammary tumorigenesis. In vivo, cell proliferation, angiogenesis, cell cycle progression, and survival markers were up-regulated in tumors by Cyp27b1 ablation, and apoptosis was decreased. AK thymoma (AKT) phosphorylation and expression of several components of nuclear factor κB (NF-κB), integrin, and signal transducer and activator of transcription 3 (STAT3) signaling pathways were increased in Cyp27b1-ablated tumors compared with nonablated controls. In vitro, 1,25(OH)2D treatment induced a strong antiproliferative action on tumor cells from both ablated and nonablated mice, accompanied by rapid disappearance of NF-κB p65 from the nucleus and segregation in the cytoplasm. In contrast, treatment with the metabolic precursor 25(OH)D was only effective against cells from nonablated mice. 25(OH)D did not inhibit growth of Cyp27b1-ablated cells, and their nuclear NF-κB p65 remained abundant. Our findings demonstrate that in-tumor CYP27B1 1-α-hydroxylase activity plays a crucial role in controlling early oncogene-mediated mammary carcinogenesis events, at least in part by modulating tumoral cell NF-κB p65 nuclear translocation. |
| Databáze: | OpenAIRE |
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