A defective homologous recombination (HR) repair program increases tumor incidence as well as providing a survival advantage in patients with breast and ovarian cancers. Here we hypothesize that the tumor-promoting side of genome maintenance programs may be contributed by a self-renewal protein, nucleostemin (NS). To address this issue, we established its functional importance in mammary tumor progression in mice and showed that mammary tumor cells become highly susceptible to replicative DNA damage following NS depletion and are protected from hydroxyurea-induced damage by NS overexpression. Breast cancer cells with basal-like characters display more reliance on NS for genome maintenance than those with luminal characters. Mechanistically, NS-deficient cells demonstrate a significantly reduced HR repair activity. TCGA analyses of human breast cancers revealed that NS is co-enriched positively with HR repair proteins and that high NS expression correlates with low HR defects and predicts poor progression-free survival and resistance to knockdown of cell-cycle checkpoint genes in triple-negative/basal-like breast cancers. This work indicates that NS constitutes a tumor-promoting genome maintenance program required for mammary tumor progression.

有缺陷的同源重组（HR）修复程序会增加肿瘤的发生率，并为乳腺癌和卵巢癌患者提供生存优势。在这里我们假设基因组维护程序的肿瘤促进方面可能是由自我更新的蛋白质核蛋白（NS）贡献的。为了解决这个问题，我们确立了其在小鼠乳腺肿瘤进展中的功能重要性，并表明乳腺肿瘤细胞在NS耗尽后变得对复制性DNA损伤高度敏感，并受到NS过表达对羟基脲诱导的损伤的保护。具有基底样特征的乳腺癌细胞比具有管腔特征的乳腺癌细胞对NS的基因组维持表现出更大的依赖性。从机制上讲，NS缺陷细胞表现出显着降低的HR修复活性。TCGA对人类乳腺癌的分析表明，NS与HR修复蛋白共富集，而高NS表达与低HR缺陷相关，并预测三联阴性/基底样乳腺癌。这项工作表明NS构成了乳腺肿瘤进展所需的促进肿瘤的基因组维持程序。