Mammary-specific ablation of Cyp24a1 inhibits development, reduces proliferation and increases sensitivity to vitamin D. Issue 189 (May 2019)

• Record Type: Journal Article
• Authors: Sheng, Lei; Turner, Andrew G.; Barratt, Kate; Kremer, Richard; Morris, Howard A.; Callen, David F.; Anderson, Paul H.; Tarulli, Gerard A.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 189(2019)
• Page Start: 240
• Page End: 247
• Publication Date: 2019-05
• Subjects: Vitamin D -- CYP24A1 -- Mammary -- Epithelium; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.01.005
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Vitamin D catabolism via Cyp24a1 modulates postnatal and pregnancy-associated mammary gland development. Cyp24a1 gene deletion in the mammary epithelium inhibits luminal epithelial proliferation but not apoptosis. Luminal mammary epithelial cells are more sensitive to 1, 25(OH)2D with the ablation of Cyp24a1 activity. Abstract: 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.