Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo.
Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo.
复制标题
钙三醇对裸鼠MCF-7乳腺癌异种移植物生长的抑制作用：体内芳香酶表达的选择性调节。
DOI：
10.1007/s12672-011-0073-7
复制
发表时间：
2011-06
影响因子：
3
通讯作者：
Feldman, David
中科院分区：
文献类型：
--
作者：
Swami, Srilatha;Krishnan, Aruna V;Wang, Jennifer Y;Jensen, Kristin;Peng, Lihong;Albertelli, Megan A;Feldman, David
骨化三醇（1,25-二羟基维生素D3）是维生素D的激素活性代谢产物，在乳腺癌（BCa）细胞中具有许多抗癌作用。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化酶调节剂（SAM），抑制BCa细胞中的雌激素合成和信号传导。我们现在研究了骨化三醇在体内单独使用和与芳香酶抑制剂（AIs）联合使用时对芳香酶表达、雌激素信号和肿瘤生长的影响。在携带MCF-7异种移植物的免疫功能受损小鼠中，增加骨化三醇剂量显示出显著的肿瘤抑制作用（肿瘤体积减少约50%至70%）。在测试的次优剂量下，阿那曲唑和来曲唑单独使用时也引起显著的肿瘤缩小。尽管与单一药物相比，骨化三醇和AIs的联合使用在统计学上显著增加了肿瘤抑制作用，但在测试的剂量下，这些药物之间的合作相互作用似乎很小。骨化三醇降低异种移植物肿瘤中芳香化酶的表达。重要的是，骨化三醇在小鼠中也起到了SAM的作用，降低了乳腺脂肪组织中的芳香化酶表达，同时增加了骨髓细胞中的芳香化酶表达，而没有改变卵巢和子宫中的芳香化酶表达。结果，骨化三醇显著降低了异种移植物肿瘤和乳腺周围脂肪组织中的雌激素水平。骨化三醇通过降低肿瘤ERα水平抑制雌激素信号传导。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协同作用调节基因表达。我们假设，当骨化三醇与AI联合治疗BCa时，累积这些骨化三醇作用将有助于产生有益效果。
Calcitriol (1,25-dihydroxyvitamin D3), 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.