Thangavelu Pulari U, Lin Cheng-Yu, Vaidyanathan Srividya, Nguyen Thu H M, Dray Eloise, Duijf Pascal H G
University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, QLD, Australia.
Oncotarget. 2017 Jul 10;8(37):62167-62182. doi: 10.18632/oncotarget.19131. eCollection 2017 Sep 22.
During cell division, chromosome segregation is facilitated by the mitotic checkpoint, or spindle assembly checkpoint (SAC), which ensures correct kinetochore-microtubule attachments and prevents premature sister-chromatid separation. It is well established that misexpression of SAC components on the outer kinetochores promotes chromosome instability (CIN) and tumorigenesis. Here, we study the expression of CENP-I, a key component of the HIKM complex at the inner kinetochores, in breast cancer, including ductal, lobular, medullary and male breast carcinomas. CENPI mRNA and protein levels are significantly elevated in estrogen receptor-positive (ER+) but not in estrogen receptor-negative (ER-) breast carcinoma. Well-established prognostic tests indicate that CENPI overexpression constitutes a powerful independent marker for poor patient prognosis and survival in ER+ breast cancer. We further demonstrate that is an E2F target gene. Consistently, it is overexpressed in -deficient breast cancers. However, CENP-I overexpression is not purely due to cell cycle-associated expression. In ER+ breast cancer cells, CENP-I overexpression promotes CIN, especially chromosome gains. In addition, in ER+ breast carcinomas the degree of CENPI overexpression is proportional to the level of aneuploidy and CENPI overexpression is one of the strongest markers for CIN identified to date. Our results indicate that overexpression of the inner kinetochore protein CENP-I promotes CIN and forecasts poor prognosis for ER+ breast cancer patients. These observations provide novel mechanistic insights and have important implications for breast cancer diagnostics and potentially therapeutic targeting.
在细胞分裂过程中，有丝分裂检查点或纺锤体组装检查点（SAC）促进染色体分离，该检查点可确保动粒与微管的正确附着，并防止姐妹染色单体过早分离。众所周知，外动粒上SAC组件的错误表达会促进染色体不稳定（CIN）和肿瘤发生。在此，我们研究了内动粒处HIKM复合体的关键组件CENP-I在乳腺癌（包括导管癌、小叶癌、髓样癌和男性乳腺癌）中的表达情况。CENPI的mRNA和蛋白质水平在雌激素受体阳性（ER+）乳腺癌中显著升高，而在雌激素受体阴性（ER-）乳腺癌中则不然。成熟的预后检测表明，CENPI过表达是ER+乳腺癌患者预后不良和生存率低的有力独立标志物。我们进一步证明 是一个E2F靶基因。一致的是，它在 缺陷的乳腺癌中过表达。然而，CENP-I过表达并非纯粹由于细胞周期相关的表达。在ER+乳腺癌细胞中，CENP-I过表达会促进CIN，尤其是染色体增加。此外，在ER+乳腺癌中，CENPI过表达的程度与非整倍体水平成正比，且CENPI过表达是迄今为止确定的CIN最强标志物之一。我们的结果表明，内动粒蛋白CENP-I的过表达会促进CIN，并预示ER+乳腺癌患者预后不良。这些观察结果提供了新的机制见解，对乳腺癌诊断及潜在的治疗靶点具有重要意义。
