HER2-positive breast cancer cells expressing elevated FAM83A are sensitive to FAM83A loss.
HER2-positive breast cancer cells expressing elevated FAM83A are sensitive to FAM83A loss.
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DOI：
10.1371/journal.pone.0176778
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Jackson MW
中科院分区：
文献类型：
--
作者：
Bartel CA;Jackson MW
HER2阳性乳腺癌（HER2+ BC）是一种预后不良的侵袭性亚型。尽管靶向HER2生长因子受体的曲妥珠单抗抗体提高了生存率，但患者通常会出现新发耐药或在初始应答后获得耐药。确定靶向HER 2信号传导的新方法对于克服曲妥珠单抗耐药性至关重要。FAM83A是一种新的癌基因，通过其赋予对EGFR疗法的抗性的能力来鉴定，EGFR疗法是与HER2密切相关的受体。此外，先前的研究在曲妥珠单抗耐药的HER2+ BC中鉴定出高酪氨酸磷酸化的FAM83A。在这里，我们发现FAM83A表达在36%的HER2+ BC肿瘤中升高。在一组HER2+ BC细胞系中，相对于亲本对照，曲妥珠单抗耐药衍生物中的FAM83A表达显著增加。shRNA介导的HER2+ BC细胞系组中FAM83A的消融抑制2D和3D细胞培养物中的HER2+ BC细胞生长，提高凋亡标志物，并抑制PI3K信号传导。然而，FAM83A敲低后的生长抑制与曲妥珠单抗敏感性无关，表明FAM83A是HER2+ BC中的关键信号传导组分，可作为曲妥珠单抗耐药和曲妥珠单抗敏感癌症的新型治疗靶点。
HER2-positive breast cancer (HER2+ BC) is an aggressive subtype with a poor prognosis. Although the antibody trastuzumab, which targets the HER2 growth factor receptor, has improved survival rates, patients often present with de novo resistance or acquire resistance after an initial response. Identifying new ways to target HER2 signaling will be critical for overcoming trastuzumab resistance. FAM83A is a novel oncogene identified by its ability to confer resistance to EGFR therapies, a receptor closely related to HER2. Moreover, a prior study identified hyper-tyrosine phosphorylated FAM83A in trastuzumab-resistant HER2+ BC. Here, we find that FAM83A expression is elevated in 36% of HER2+ BC tumors. In a panel of HER2+ BC cell lines, FAM83A expression is significantly increased in the trastuzumab-resistant derivatives relative to parental controls. shRNA-mediated ablation of FAM83A in the panel of HER2+ BC cell lines suppresses HER2+ BC cell growth in both 2D and 3D cell cultures, elevates apoptosis markers, and suppresses PI3K signaling. Growth inhibition following FAM83A knock-down, however, was independent of trastuzumab sensitivity, suggesting that FAM83A is a key signaling component in HER2+ BCs that could serve as a novel therapeutic target in both trastuzumab-resistant and trastuzumab-sensitive cancers.