Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, ON, Canada.
Breast Cancer Res Treat. 2012 Jun;133(2):563-73. doi: 10.1007/s10549-011-1816-4. Epub 2011 Oct 14.
Insulin-like growth factor binding protein 7 (IGFBP7) has been shown to be a tumor suppressor in a variety of cancers. We previously have shown that IGFBP7 expression is inversely correlated with disease progression and poor outcome in breast cancer. Overexpression of IGFBP7 in MDA-MB-468, a triple-negative breast cancer (TNBC) cell line, resulted in inhibition of growth and migration. Xenografted tumors bearing ectopic IGFBP7 expression were significantly growth-impaired compared to IGFBP7-negative controls, which suggested that IGFBP7 treatment could inhibit breast cancer cell growth. To confirm this notion, 14 human patient primary breast tumors were analyzed by qRTPCR for IGFBP7 expression. The TNBC tumors expressed the lowest levels of IGFBP7 expression, which also correlated with higher tumorigenicity in mice. Furthermore, when breast cancer cell lines were treated with IGFBP7, only the TNBC cell lines were growth inhibited. Treatment of NOD/SCID mice harboring xenografts of TNBC cells with IGFBP7 systemically every 3-4 days inhibited tumorigenesis, with associated anti-angiogenic effects, together with increased apoptosis. Upon examining the mechanism of IGFBP7-mediated growth inhibition in TNBC cells, we found that cells not only were arrested in G1 phase of the cell cycle but also underwent senescence as a result of treatment with IGFBP7. Interestingly, IGFBP7 treatment was also associated with strong activation of the stress-associated p38 MAPK pathway, together with upregulation of p53 and the cyclin-dependent protein kinase (CDK) inhibitor, p21(cip1). Prolonged treatment of cells with IGFBP7 resulted in increased cell death, marked by an increase in apoptotic cells and associated cleaved PARP. This is the first study showing that exogenous IGFBP7 inhibits TNBC cell growth both in vitro and in vivo. Taken together, these results suggest IGFBP7 treatment might have therapeutic potential for TNBC.
胰岛素样生长因子结合蛋白 7（IGFBP7）已被证明在多种癌症中是一种肿瘤抑制因子。我们之前的研究表明，IGFBP7 的表达与乳腺癌的疾病进展和不良预后呈负相关。在三阴性乳腺癌（TNBC）细胞系 MDA-MB-468 中过表达 IGFBP7 会导致生长和迁移受到抑制。与 IGFBP7 阴性对照相比，异位表达 IGFBP7 的异种移植瘤的生长明显受损，这表明 IGFBP7 治疗可能抑制乳腺癌细胞的生长。为了证实这一观点，我们通过 qRT-PCR 分析了 14 个人类原发性乳腺癌肿瘤的 IGFBP7 表达。TNBC 肿瘤表达的 IGFBP7 水平最低，这也与在小鼠中更高的致瘤性相关。此外，当用 IGFBP7 处理乳腺癌细胞系时，只有 TNBC 细胞系的生长受到抑制。每隔 3-4 天用 IGFBP7 系统地治疗携带 TNBC 细胞异种移植的 NOD/SCID 小鼠，可抑制肿瘤发生，并伴有抗血管生成作用，同时增加细胞凋亡。在研究 IGFBP7 介导的 TNBC 细胞生长抑制的机制时，我们发现细胞不仅在细胞周期的 G1 期被阻滞，而且由于 IGFBP7 的治疗还经历了衰老。有趣的是，IGFBP7 治疗还与应激相关的 p38 MAPK 途径的强烈激活以及 p53 和细胞周期蛋白依赖性蛋白激酶（CDK）抑制剂 p21（cip1）的上调有关。长时间用 IGFBP7 处理细胞会导致细胞死亡增加，表现为凋亡细胞增加和相关的 PARP 切割增加。这是第一项表明外源性 IGFBP7 可在体外和体内抑制 TNBC 细胞生长的研究。总之，这些结果表明 IGFBP7 治疗可能对 TNBC 具有治疗潜力。
