CYP24A1型
维生素D与神经学
癌症研究
骨化三醇受体
乳腺
生物
细胞凋亡
内分泌学
条件基因敲除
内科学
上皮
细胞生长
乳腺癌
癌症
细胞生物学
医学
表型
生物化学
遗传学
基因
作者
Lei Sheng,Andrew G. Turner,Kate R. Barratt,Richard Kremer,Howard A. Morris,David F. Callen,Paul Anderson,Gerard A. Tarulli
标识
DOI:10.1016/j.jsbmb.2019.01.005
摘要
Active vitamin D (1,25(OH)2D) has been shown to regulate numerous cell processes in mammary cells. Degradation of 1,25(OH)2D is initiated by the mitochondrial enzyme, 25-hydroxyvitamin D 24-hydroxylase (CYP24 A1), and provides local control of 1,25(OH)2D bioactivity. Several reports of the association between elevated CYP24 A1 activity and breast cancer incidence, suggest that CYP24 A1 may be a target for therapeutic intervention. Whether CYP24 A1 activity within the mammary epithelium regulates 1,25(OH)2D levels and mammary gland development is yet to shown. We have used a conditional knockout of the Cyp24a1 gene specifically in the mammary epithelium to demonstrate reduced terminal end bud number, ductal outgrowth and branching during puberty and alveologenesis at early pregnancy, by inhibiting proliferation but not apoptosis in both basal and luminal MECs. In vitro study showed increased sensitivity of luminal MECs to lower levels of 1,25(OH)2D with the ablation of Cyp24a1 activity. In summary, Cyp24a1 within MECs plays an important role in modulating postnatal and pregnancy-associated mammary gland development which provides support for inhibiting CYP24 A1 as a potential approach to activating the vitamin D pathway in breast cancer prevention and therapy.
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