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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Ruminant Diseases and Immunology Research » Research » Publications at this Location » Publication #322648

Title: Tumoral vitamin D synthesis by CYP27B1 1-alpha-hydroxylase delays mammary tumor progression in the PyMT-MMTV mouse model and its action involves NF-kappaB modulation

Author
item LI, JIARONG - McGill University - Canada
item LUCO, AIMEE-LEE - McGill University - Canada
item OCHIETTI, BENOIT - McGill University - Canada
item FADHIL, IBTIHAL - McGill University - Canada
item CAMIRAND, ANNE - McGill University - Canada
item Reinhardt, Timothy
item ST-ARNAUD, RENE - Shriners Hospital For Children
item MULLER, WILLIAM - McGill University - Canada
item KREMER, RICHARD - McGill University - Canada

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/25/2016
Publication Date: 4/27/2016
Publication URL: http://handle.nal.usda.gov/10113/62884
Citation: Li, J., Luco, A., Ochietti, B., Fadhil, I., Camirand, A., Reinhardt, T.A., St-Arnaud, R., Muller, W., Kremer, R. 2016. Tumoral vitamin D synthesis by CYP27B1 1-alpha-hydroxylase delays mammary tumor progression in the PyMT-MMTV mouse model and its action involves NF-kappaB modulation. Endocrinology. doi: 10.1210/en.2015-1824.

Interpretive Summary: We know that vitamin D and in its activated form promotes some innate immune functions that might be beneficial in infections. However little else is clear as to active vitamin D's role in general mammary function. Here local mammary production of activated vitamin D was inhibited and the results were greater mammary cell growth along with decreases in mammary cell death. For this mouse model of breast cancer this resulted in an increase in breast cancer. For normal mammary physiology the data indicated that local production of the active form of vitamin D may play as yet uninvestigated roles in mammary development important to lactation.

Technical Abstract: Biologically-active vitamin D (1,25(OH)2D) is synthetized from inactive prohormone 25(OH)D by the enzyme CYP27B1 1-a-hydroxylase in kidney and several extra-renal tissues including breast. While 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 PyMT-MMTV mouse breast cancer model. Targeted ablation of Cyp27b1 was accompanied by significant acceleration in initiation of spontaneous breast tumorigenesis. In vivo, cell proliferation, angiogenesis, cell cycle progression and survival markers were upregulated in tumors by Cyp27b1 ablation, and apoptosis was decreased. Akt phosphorylation and expression of several components of NF-kB, integrin and STAT3 signaling pathways were increased in Cyp27b1–ablated tumors compared to non-ablated controls. In vitro, 1,25 (OH)2D treatment induced a strong antiproliferative action on tumor cells from both ablated and non-ablated mice, accompanied by rapid disappearance of NF-kB 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 non-ablated mice. 25(OH)D did not inhibit growth of Cyp27b1-ablated cells, and their nuclear NF-kB p65 remained abundant. Our findings demonstrate that in-tumor CYP27B1 1-a-17 hydroxylase activity plays a crucial role in controlling early oncogene-mediated breast carcinogenesis events, at least in part by modulating tumoral cell NF-kB p65 nuclear translocation.