Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells.
Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells.
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乳腺上皮细胞中同时发生的 HER2 和突变 PIK3CA 的协同致癌效应和细胞信号传导串扰。
DOI：
10.3892/ijo.2017.4108
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发表时间：
2017-10
影响因子：
5.2
通讯作者：
Wu G
中科院分区：
文献类型：
--
作者：
Dong L;Meng F;Wu L;Mitchell AV;Block CJ;Zhang B;Craig DB;Jang H;Chen W;Yang Q;Wu G
尽管PI3K致癌突变的发生率在乳腺癌中很突出（20-30%），但仅针对这一信号通路的药理作用未能提供有意义的临床益处。为了更好地理解和解决这个问题，我们进行了全基因组分析，研究突变PI3K与其他基因扩增事件的关系。与PIK3CA突变相关的最重要的拷贝数增加事件之一是包含HER2的17号染色体内的区域。为了研究共同发生的PIK3CA- h1047r和/或HER2基因的致癌作用和细胞信号调节，我们建立了异位表达突变PIK3CA、HER2或两者遗传改变的细胞模型。我们观察到，具有两种遗传改变的细胞比单独具有任何一种遗传改变的细胞表现出更高的侵袭性和侵袭能力。此外，我们发现HER2抑制剂（CP-724714）和pan PI3K抑制剂（LY294002）联合使用在抑制细胞增殖和集落形成方面比单独使用任何一种抑制剂更有效。值得注意的是，通过Affymetric微阵列分析，发现HER2、PIK3CA突变体细胞和具有这两种遗传改变的细胞有四种共同的细胞信号通路。此外，细胞周期检查点控制信号通路和DNA损伤反应信号通路的丰富表明，这两种基因改变的细胞获得了更显著的复制应激。我们的研究表明，致癌HER2和突变PIK3CA的共同出现共同推动了乳腺癌的进展。具有这两种基因改变的细胞获得了复制应激的额外特征，这可能为癌症诊断和治疗开辟新的机会。
Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20-30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment.
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影响因子：
6.7
作者：
Jeon SM;Hay N
通讯作者：
Hay N
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3.6
作者：
Bachman, KE;Argani, P;Park, BH
通讯作者：
Park, BH
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通讯作者：
Kuhajda, F. P.