Quantitative phosphoproteomics reveals genistein as a modulator of cell cycle and DNA damage response pathways in triple-negative breast cancer cells

被引:41
作者
Fang, Yi [1 ]
Zhang, Qian [6 ]
Wang, Xin [1 ]
Yang, Xue [1 ]
Wang, Xiangyu [1 ]
Huang, Zhen [2 ]
Jiao, Yuchen [3 ,4 ,5 ]
Wang, Jing [1 ,5 ]
机构
[1] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Breast Surg Oncol, Beijing 100730, Peoples R China
[2] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Abdominal Surg Oncol, Beijing 100730, Peoples R China
[3] Chinese Acad Med Sci, Canc Inst & Hosp, Lab Cell & Mol Biol, Beijing 100730, Peoples R China
[4] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing 100730, Peoples R China
[5] Peking Union Med Coll, Nanli 17, Beijing 100021, Peoples R China
[6] Capital Med Univ, Beijing Tiantan Hosp, Dept Gastroenterol, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
genistein; tandem mass tag; quantitative phosphoproteomics; triple-negative breast cancer; cell cycle; DNA damage response; BRCA1; CDK1; ataxia telangiectasia; NF-KAPPA-B; CENP-A; GENE-FUNCTION; PROTEIN; CHECKPOINT; MDA-MB-231; BRCA1; PHOSPHORYLATION; GROWTH; IDENTIFICATION;
D O I
10.3892/ijo.2016.3327
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Around one sixth of breast cancer cases are classified as triple-negative breast cancer (TNBC), named after the absence of the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2); however, patients with TNBC suffer from poor clinical outcome and shortage of targeted therapy. Genistein, an estrogenic soy isoflavone, shows anticancer effects in TNBC cells such as inducing G2/M cell cycle arrest and apoptosis. However, the underlying mechanism of its anticancer effects is poorly understood and its elucidation can help the development of novel therapeutic strategies for TNBC. In this study, by combining isobaric tag-based TMT labeling with titanium dioxide-based phosphopeptide enrichment, we quantitated 5,445 phosphorylation sites on 2,008 phosphoproteins in the TNBC cell line MDA-MB-231, upon genistein treatment. Our analysis revealed 332 genistein-regulated phosphorylation sites on 226 proteins. Our data show that genistein can regulate several biological processes during the cell cycle, including DNA replication, cohesin complex cleavage, and kinetochore formation. Furthermore, genistein can also activate DNA damage response, including activation of ATR and BRCA1 complex. Overall, our study presents evidence at a phosphoproteomic level that genistein is able to inhibit TNBC cell growth by regulating the cell cycle and DNA damage response in a more complex manner. Our findings help elucidate the mechanisms through which genistein exerts its anticancer effects in TNBC cells.
引用
收藏
页码:1016 / 1028
页数:13
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