Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States.
Steroids. 2012 Sep;77(11):1107-12. doi: 10.1016/j.steroids.2012.06.005. Epub 2012 Jul 16.
Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+BCa in women.
骨化三醇（1,25-二羟维生素 D(3)），维生素 D 的活性形式，可抑制包括乳腺癌（BCa）细胞在内的许多恶性细胞的生长。骨化三醇抗癌作用的机制包括细胞周期停滞、刺激细胞凋亡和抑制侵袭、转移和血管生成。此外，我们发现了骨化三醇作用的新途径，这些途径在抑制雌激素受体阳性（ER+）BCa 细胞生长方面尤为相关。骨化三醇抑制 COX-2 的表达并增加 15-PGDH 的表达，从而降低炎症性前列腺素（PGs）的水平。我们的体外和体内研究表明，骨化三醇通过启动子 II 直接抑制芳香酶转录以及由于 PGs 水平降低的间接作用，降低芳香酶的表达，芳香酶是 BCa 细胞和乳腺癌周围乳腺脂肪组织中选择性催化雌激素合成的酶。PGs 是通过启动子 II 主要刺激芳香酶转录的刺激物。骨化三醇下调 ERα 的表达，从而减弱 BCa 细胞中的雌激素信号，包括雌激素提供的增殖刺激。因此，骨化三醇抑制雌激素合成和信号以及其抗炎作用将在抑制 ER+BCa 中发挥重要作用。我们假设由于乳腺细胞中存在 25-羟维生素 D-1α-羟化酶（CYP27B1），膳食维生素 D 会表现出类似的抗癌活性，从而确保循环 25-羟维生素 D 转化为局部乳腺微环境中的骨化三醇，从而以旁分泌方式抑制 BCa 生长。细胞培养和小鼠体内数据强烈表明，骨化三醇和膳食维生素 D 将在预防和/或治疗女性 ER+BCa 中发挥有益作用。
