Blouin Marie-José, Bazile Miguel, Birman Elena, Zakikhani Mahvash, Florianova Livia, Aleynikova Olga, Powell David R, Pollak Michael
Lady Davis Institute for Medical Research of the Jewish General Hospital, Room E-423, 3755 Cote-Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada,
Breast Cancer Res Treat. 2015 Feb;149(3):577-85. doi: 10.1007/s10549-015-3268-8. Epub 2015 Jan 23.
Insulin-like growth factor binding protein-3 (IGFBP-3) is an important carrier protein for insulin-like growth factors (IGFs) in the circulation. IGFBP-3 antagonizes the growth-promoting and anti-apoptotic activities of IGFs in experimental systems, but in certain contexts can increase IGF bioactivity, probably by increasing its half-life. The goal of this study was to investigate the role of IGFBP-3 in breast carcinogenesis and breast cancer metastasis. In the first part of the study, we exposed IGFBP-3 knockout and wild-type female mice to dimethylbenz[a]anthracene (DMBA) and followed them for appearance of primary tumors for up to 13 months. In the second part, mice of each genotype received an IV injection of 4T1 mammary carcinoma cells and then lung nodules were counted. Our results show that IGFBP-3 knockout mice developed breast tumors significantly earlier than the wild-type (13.9 ± 1.1 versus 22.5 ± 3.3 weeks, respectively, P = 0.0144), suggesting tumor suppression activity of IGFBP-3. In tumors of IGFBP-3 knockout mice, levels of phospho-AKT(Ser473) were increased compared to wild-type mice. The lung metastasis assay showed significantly more and larger lung nodules in IGFBP-3 knockout mice than in wild-type mice. While we observed increased levels of IGFBP-5 protein in the IGFBP-3 knockout mice, our findings suggest that this was not sufficient to completely compensate for the absence of IGFBP-3. Even though knockout of IGFBP-3 is associated with only a subtle phenotype under control conditions, our results reveal that loss of this gene has measurable effects on breast carcinogenesis and breast cancer metastasis.
胰岛素样生长因子结合蛋白-3（IGFBP-3）是循环中胰岛素样生长因子（IGFs）的重要载体蛋白。在实验系统中，IGFBP-3可拮抗IGFs的促生长和抗凋亡活性，但在某些情况下可能通过延长其半衰期来增加IGF的生物活性。本研究的目的是探讨IGFBP-3在乳腺癌发生和转移中的作用。在研究的第一部分，我们将IGFBP-3基因敲除和野生型雌性小鼠暴露于二甲基苯并[a]蒽（DMBA），并跟踪它们长达13个月，观察原发性肿瘤的出现情况。在第二部分中，每种基因型的小鼠接受静脉注射4T1乳腺癌细胞，然后计数肺结节。我们的结果表明，IGFBP-3基因敲除小鼠发生乳腺肿瘤的时间明显早于野生型小鼠（分别为13.9±1.1周和22.5±3.3周，P = 0.0144），提示IGFBP-3具有肿瘤抑制活性。与野生型小鼠相比，IGFBP-3基因敲除小鼠肿瘤中的磷酸化AKT（Ser473）水平升高。肺转移实验显示，IGFBP-3基因敲除小鼠的肺结节明显多于野生型小鼠，且体积更大。虽然我们观察到IGFBP-3基因敲除小鼠中IGFBP-5蛋白水平升高，但我们的研究结果表明，这不足以完全弥补IGFBP-3的缺失。尽管在对照条件下敲除IGFBP-3仅与轻微的表型相关，但我们的结果表明，该基因的缺失对乳腺癌发生和转移具有可测量的影响。
