Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan, United States of America.
PLoS One. 2013 Aug 14;8(8):e71258. doi: 10.1371/journal.pone.0071258. eCollection 2013.
Mitochondria play important roles in cancer progression and have emerged as viable targets for cancer therapy. Increasing levels of the outer mitochondrial membrane protein, 18-kDa translocator protein (TSPO), are associated with advancing breast cancer stage. In particular, higher TSPO levels are found in estrogen receptor (ER)-negative breast tumors, compared with ER-positive tumors. In this study, we sought to define the roles of TSPO in the acquisition of breast cancer malignancy. Using a three-dimensional Matrigel culture system, we determined the impact of elevated TSPO levels on mammary epithelial morphogenesis. Our studies demonstrate that stable overexpression of TSPO in mammary epithelial MCF10A acini drives proliferation and provides partial resistance to luminal apoptosis, resulting in enlarged acinar structures with partially filled lumen that resemble early stage breast lesions leading to breast cancer. In breast cancer cell lines, TSPO silencing or TSPO overexpression significantly altered the migratory activity. In addition, we found that combination treatment with the TSPO ligands (PK 11195 or Ro5-4864) and lonidamine, a clinical phase II drug targeting mitochondria, decreased viability of ER-negative breast cancer cell lines. Taken together, these data demonstrate that increases in TSPO levels at different stages of breast cancer progression results in the acquisition of distinct properties associated with malignancy. Furthermore, targeting TSPO, particularly in combination with other mitochondria-targeting agents, may prove useful for the treatment of ER-negative breast cancer.
线粒体在癌症进展中发挥着重要作用，已成为癌症治疗的可行靶点。细胞外线粒体膜蛋白 18kDa 转位蛋白（TSPO）水平的升高与乳腺癌的进展阶段相关。特别是，与 ER 阳性肿瘤相比，ER 阴性乳腺癌肿瘤中 TSPO 水平更高。在这项研究中，我们试图确定 TSPO 在获得乳腺癌恶性肿瘤中的作用。使用三维 Matrigel 培养系统，我们确定了 TSPO 水平升高对乳腺上皮形态发生的影响。我们的研究表明，在乳腺上皮 MCF10A 小泡中稳定过表达 TSPO 可驱动增殖，并提供对管腔凋亡的部分抗性，导致具有部分填充管腔的扩大小泡结构，类似于导致乳腺癌的早期阶段病变。在乳腺癌细胞系中，TSPO 沉默或 TSPO 过表达显著改变了迁移活性。此外，我们发现 TSPO 配体（PK 11195 或 Ro5-4864）与 lonidamine 的联合治疗（一种针对线粒体的临床 II 期药物）降低了 ER 阴性乳腺癌细胞系的活力。总之，这些数据表明，乳腺癌进展不同阶段 TSPO 水平的升高导致获得与恶性肿瘤相关的不同特性。此外，靶向 TSPO，特别是与其他靶向线粒体的药物联合使用，可能对治疗 ER 阴性乳腺癌有用。
