Neff Ryan A, Bosch-Gutierrez Almudena, Sun Yifei, Katsyv Igor, Song Won-Min, Wang Minghui, Walsh Martin J, Zhang Bin
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
NAR Cancer. 2023 Jul 10;5(3):zcad036. doi: 10.1093/narcan/zcad036. eCollection 2023 Sep.
Breast cancer is the most common type of cancer among women worldwide, and it is estimated that 294 000 new diagnoses and 37 000 deaths will occur each year in the United States alone by 2030. Large-scale genomic studies have identified a number of genetic loci with alterations in breast cancer. However, identification of the genes that are critical for tumorgenicity still remains a challenge. Here, we perform a comprehensive functional multi-omics analysis of somatic mutations in breast cancer and identify previously unknown key regulators of breast cancer tumorgenicity. We identify dysregulation of , an E3 ubiquitin ligase and an upstream regulator of mTOR signaling, is accompanied with decreased disease-free survival. We validate as a key target through depletion siRNA using apoptosis assays in MCF10A, MCF7 and T47D cells. We demonstrate that MYCBP2 loss is associated with resistance to apoptosis from cisplatin-induced DNA damage and cell cycle changes, and that CHEK1 inhibition can modulate MYCBP2 activity and caspase cleavage. Furthermore, we show that MYCBP2 knockdown is associated with transcriptomic responses in and in apoptosis genes and interleukins. Therefore, we show that is an important genetic target that represents a key node regulating multiple molecular pathways in breast cancer corresponding with apparent drug resistance in our study.
乳腺癌是全球女性中最常见的癌症类型，据估计，仅在美国到2030年每年就会有29.4万例新诊断病例和3.7万例死亡。大规模基因组研究已经确定了一些在乳腺癌中发生改变的基因位点。然而，确定对肿瘤发生至关重要的基因仍然是一项挑战。在此，我们对乳腺癌中的体细胞突变进行了全面的功能多组学分析，并确定了先前未知的乳腺癌肿瘤发生关键调节因子。我们发现，一种E3泛素连接酶和mTOR信号的上游调节因子的失调与无病生存期的降低有关。我们通过在MCF10A、MCF7和T47D细胞中使用凋亡检测的缺失siRNA验证了作为一个关键靶点。我们证明，MYCBP2的缺失与顺铂诱导的DNA损伤和细胞周期变化导致的凋亡抗性有关，并且CHEK1抑制可以调节MYCBP2活性和半胱天冬酶切割。此外，我们表明，MYCBP2的敲低与和凋亡基因及白细胞介素中的转录组反应有关。因此，我们表明是一个重要的遗传靶点，代表了调节乳腺癌中多个分子途径的关键节点，在我们的研究中与明显的耐药性相对应。
