Division of Hematology-Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cancer Gene Ther. 2013 May;20(5):298-307. doi: 10.1038/cgt.2013.21. Epub 2013 Apr 26.
Stathmin is the founding member of a family of microtubule-destabilizing proteins that have a critical role in the regulation of mitosis. Stathmin is expressed at high levels in breast cancer and its overexpression is linked to disease progression. Although there is a large body of evidence to support a role for stathmin in breast cancer progression, the validity of stathmin as a viable therapeutic target for breast cancer has not been investigated. Here, we used a bicistronic adenoviral vector that co-expresses green fluorescent protein and a ribozyme that targets stathmin messenger RNA in preclinical breast cancer models with different estrogen receptor (ER) status. We examined the effects of anti-stathmin ribozyme on the malignant phenotype of breast cancer cells in vitro and in xenograft models in vivo both as a single agent and in combination with chemotherapeutic agents. Adenovirus-mediated gene transfer of anti-stathmin ribozyme resulted in a dose-dependent inhibition of proliferation and clonogenicity associated with a G2/M arrest and increase in apoptosis in both ER-positive and ER-negative breast cancer cell lines. This inhibition was markedly enhanced when stathmin-inhibited breast cancer cells were exposed to low concentrations of taxol, which resulted in virtually complete loss of the malignant phenotype. Interestingly, breast cancer xenografts treated with low doses of anti-stathmin therapy and taxol showed regression in a majority of tumors, while some tumors stopped growing completely. In contrast, combination of anti-stathmin ribozyme and adriamycin resulted in only a modest inhibition of growth in vitro and in breast cancer xenografts in vivo. Although inhibition of tumor growth was observed in both the combination treatment groups compared with groups treated with single agent alone, combination of anti-stathmin therapy and taxol had a more profound inhibition of tumorigenicity, as both agents target the microtubule pathway. Clinically, these findings are highly relevant because taxol is one of the most active chemotherapeutic agents in breast cancer. These studies provide the proof-of-principle that stathmin provides an attractive molecular target, which could serve as a primary focus of novel approaches to breast cancer.
微管去稳定蛋白家族的创始成员之一，在有丝分裂调控中具有关键作用。Stathmin 在乳腺癌中表达水平较高，其过表达与疾病进展有关。尽管有大量证据支持 stathmin 在乳腺癌进展中的作用，但 stathmin 是否可作为乳腺癌的可行治疗靶点尚未得到研究。在这里，我们使用了一种双顺反子腺病毒载体，该载体共表达绿色荧光蛋白和针对 stathmin 信使 RNA 的核酶，在具有不同雌激素受体 (ER) 状态的临床前乳腺癌模型中。我们检查了抗 stathmin 核酶在体外和体内异种移植模型中作为单一药物以及与化疗药物联合使用对乳腺癌细胞恶性表型的影响。腺病毒介导的抗 stathmin 核酶基因转移导致增殖和集落形成能力呈剂量依赖性抑制，与 G2/M 期阻滞和凋亡增加有关，这在 ER 阳性和 ER 阴性乳腺癌细胞系中均有体现。当 stathmin 抑制的乳腺癌细胞暴露于低浓度紫杉醇时，这种抑制作用明显增强，导致恶性表型几乎完全丧失。有趣的是，用低剂量抗 stathmin 治疗和紫杉醇治疗的乳腺癌异种移植瘤在大多数肿瘤中出现消退，而一些肿瘤则完全停止生长。相比之下，抗 stathmin 核酶和阿霉素联合治疗仅在体外和体内乳腺癌异种移植瘤中表现出适度的生长抑制。尽管与单独使用单一药物的组相比，联合治疗组观察到肿瘤生长抑制，但抗 stathmin 治疗和紫杉醇的联合治疗对肿瘤发生具有更深远的抑制作用，因为这两种药物均靶向微管途径。从临床角度来看，这些发现非常重要，因为紫杉醇是乳腺癌中最有效的化疗药物之一。这些研究提供了原理证明，即 stathmin 提供了一个有吸引力的分子靶点，可作为乳腺癌新方法的主要焦点。
