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Abstract：
The aberrant function of ATP-dependent chromatin remodeler INO80 has been implicated in multiple types of cancers by altering chromatin architecture and gene expression; however, the underlying mechanism of the functional involvement of INO80 mutation in cancer etiology, especially in breast cancer, remains unclear. In the present study, we have performed a weighted gene co-expression network analysis (WCGNA) to investigate links between INO80 expression and breast cancer sub-classification and progression. Our analysis revealed that INO80 repression is associated with differential responsiveness of estrogen receptors (ERs) depending upon breast cancer subtype, ER networks, and increased risk of breast carcinogenesis. To determine whether INO80 loss induces breast tumors, a conditional INO80-knockout (INO80 cKO) mouse model was generated using the Cre-loxP system. Phenotypic characterization revealed that INO80 cKO led to reduced branching and length of the mammary ducts at all stages. However, the INO80 cKO mouse model had unaltered lumen morphology and failed to spontaneously induce tumorigenesis in mammary gland tissue. Therefore, our study suggests that the aberrant function of INO80 is potentially associated with breast cancer by modulating gene expression. INO80 mutation alone is insufficient for breast tumorigenesis.
摘要：
ATP依赖性染色质重塑剂INO80的异常功能通过改变染色质结构和基因表达而与多种类型的癌症有关；然而，INO80突变在癌症病因学中的功能参与的潜在机制，尤其是在乳腺癌中，尚不清楚。在本研究中,我们进行了加权基因共表达网络分析(WCGNA),以研究INO80表达与乳腺癌亚分类和进展之间的联系.我们的分析显示，INO80抑制与取决于乳腺癌亚型的雌激素受体（ER）的差异反应相关。ER网络,和乳腺癌发生的风险增加。为了确定INO80丢失是否会引起乳腺肿瘤，使用Cre-loxP系统产生条件INO80敲除(INO80cKO)小鼠模型。表型表征表明，INO80cKO导致各个阶段乳腺导管的分支和长度减少。然而,INO80cKO小鼠模型的管腔形态未改变，未能自发诱导乳腺组织中的肿瘤发生。因此,我们的研究提示INO80的异常功能可能通过调节基因表达与乳腺癌相关.单独的INO80突变不足以用于乳腺肿瘤发生。
