Department of Medicine-Endocrinology, Stanford University School of Medicine, Room S025, 300 Pasteur Drive, Stanford, CA 94305-5103, USA.
Horm Cancer. 2011 Jun;2(3):190-202. doi: 10.1007/s12672-011-0073-7.
Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ERα levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa.
骨化三醇（1,25-二羟维生素 D(3)）是维生素 D 的活性代谢物，在乳腺癌（BCa）细胞中具有多种抗癌作用。我们之前使用细胞培养模型表明，骨化三醇作为选择性芳香酶调节剂（SAM），抑制 BCa 细胞中的雌激素合成和信号转导。我们现在研究了骨化三醇在体内对芳香酶表达、雌激素信号转导和肿瘤生长的影响，单独使用和与芳香酶抑制剂（AIs）联合使用时的效果。在携带 MCF-7 异种移植物的免疫功能低下的小鼠中，递增剂量的骨化三醇表现出显著的肿瘤抑制作用（肿瘤体积减少约 50%至 70%）。在测试的亚最佳剂量下，阿那曲唑和来曲唑单独使用时也会导致肿瘤明显缩小。尽管与单一药物相比，骨化三醇与 AIs 的组合导致肿瘤抑制作用呈统计学显著增加，但在测试剂量下，这些药物之间的协同相互作用似乎很小。骨化三醇降低了异种移植物肿瘤中的芳香酶表达。重要的是，骨化三醇在小鼠中也作为 SAM 发挥作用，降低乳腺脂肪组织中的芳香酶表达，同时增加骨髓细胞中的芳香酶表达，而不改变卵巢和子宫中的芳香酶表达。结果，骨化三醇显著降低了异种移植物肿瘤和周围乳腺脂肪组织中的雌激素水平。此外，骨化三醇通过降低肿瘤 ERα 水平抑制雌激素信号转导。肿瘤基因表达的变化揭示了骨化三醇对炎症和生长信号通路的抑制作用，并表明骨化三醇与 AIs 之间存在协同作用，可调节基因表达。我们假设，当骨化三醇与 AI 联合用于治疗 BCa 时，这些骨化三醇的作用累积起来会产生有益的效果。
