Department of Pharmacology and Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Carcinogenesis. 2011 Mar;32(3):359-67. doi: 10.1093/carcin/bgq267. Epub 2010 Dec 16.
Molecular effects of obesity, a well-established risk factor for breast cancer progression, are mediated by adipocytokine leptin. Given the important role of leptin in breast cancer growth and metastasis, novel strategies to antagonize biological effects of this adipocytokine are much desired. We showed previously that benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables (e.g. garden cress), confers significant protection against mammary carcinogenesis in a transgenic mouse model. The present study provides first evidence for the efficacy of BITC against oncogenic effects of leptin. The BITC treatment circumvented leptin-induced clonogenicity and anchorage-independent growth of MDA-MB-231 and MCF-7 human breast cancer cells. Leptin-stimulated migration and invasion of these cells was also inhibited in the presence of BITC. Analysis of the underlying molecular mechanisms revealed that BITC treatment suppressed leptin-induced Stat3 phosphorylation and cyclin D1 transactivation. The BITC-mediated inhibition of MDA-MB-231 xenograft growth correlated with a modest yet significant decrease in levels of Tyr705 phosphorylated Stat3. The BITC treatment efficiently inhibited Stat3 and SRC1 recruitment to cyclin D1 promoter in a chromatin immunoprecipitation analysis. Furthermore, overexpression of constitutively active Stat3 imparted significant protection against BITC-mediated inhibition of cyclin D1 transactivation, whereas RNA interference of Stat3 resulted in a significant increase in BITC-mediated inhibition of cyclin D1 transactivation in the presence of leptin. These results indicate that Stat3 plays an important role in BITC-mediated inhibition of leptin-induced cyclin D1 transactivation. In conclusion, BITC could potentially be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.
肥胖是乳腺癌进展的一个既定风险因素，其分子作用是由脂肪细胞因子瘦素介导的。鉴于瘦素在乳腺癌生长和转移中的重要作用，人们非常希望寻找拮抗这种脂肪细胞因子生物学作用的新策略。我们之前已经表明，苯乙基异硫氰酸酯（BITC）是可食用十字花科蔬菜（例如西洋菜）的一种成分，可在转基因小鼠模型中对乳腺癌发生提供显著保护。本研究首次提供了 BITC 对抗瘦素致癌作用的功效证据。BITC 处理可避免瘦素诱导的 MDA-MB-231 和 MCF-7 人乳腺癌细胞的集落形成和锚定非依赖性生长。在存在 BITC 的情况下，瘦素刺激这些细胞的迁移和侵袭也被抑制。对潜在分子机制的分析表明，BITC 处理抑制了瘦素诱导的 Stat3 磷酸化和细胞周期蛋白 D1 的反式激活。BITC 介导的 MDA-MB-231 异种移植物生长抑制与 Tyr705 磷酸化 Stat3 的水平适度但显著降低相关。BITC 处理在染色质免疫沉淀分析中有效地抑制了 Stat3 和 SRC1 向细胞周期蛋白 D1 启动子的募集。此外，组成型激活 Stat3 的过表达赋予了对 BITC 介导的细胞周期蛋白 D1 反式激活抑制的显著保护，而在存在瘦素的情况下，Stat3 的 RNA 干扰导致 BITC 介导的细胞周期蛋白 D1 反式激活抑制显著增加。这些结果表明 Stat3 在 BITC 介导的抑制瘦素诱导的细胞周期蛋白 D1 反式激活中起重要作用。总之，BITC 可能是肥胖患者中高水平瘦素的乳腺癌的一种合理治疗策略。
