FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice
FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice
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DOI：
10.1172/jci60498
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Bissell, Mina J.
中科院分区：
文献类型：
--
作者：
Lee, Sun-Young;Meier, Roland;Bissell, Mina J.
乳腺癌通常会对EGFR-酪氨酸激酶抑制剂（EGFR-TKI）产生耐药性;然而，这种耐药性的机制在很大程度上仍然未知。我们推测耐药可能至少部分源于激活EGFR下游信号传导的分子改变。使用屏幕来测量恶性细胞在3D凝胶中向表型非恶性细胞的逆转，我们将FAM 83 A鉴定为能够赋予对EGFR-TKI的抗性的候选癌症相关基因。癌细胞中的FAM 83 A过表达增加了增殖和侵袭，并在培养的细胞和动物中赋予了EGFR-TKI抗性。在体内EGFR-TKI处理后存活的肿瘤细胞具有上调的FAM 83 A水平。此外，FAM 83 A过表达显著增加了培养细胞中转化灶的数量和大小以及软琼脂中的锚定非依赖性生长。相反，癌细胞中的FAM 83 A缺失导致恶性表型逆转，延迟小鼠中的肿瘤生长，并使细胞对EGFR-TKI更敏感。对已发表的临床数据的分析揭示了FAM 83 A高表达与乳腺癌患者预后不良之间的相关性。我们发现FAM 83 A与MAPK上游和EGFR下游的c-RAF和PI 3 K p85相互作用并引起其磷酸化。这些数据提供了肿瘤细胞可以变得EGFR-TKI耐药的另外的机制。
Breast cancers commonly become resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, the mechanisms of this resistance remain largely unknown. We hypothesized that resistance may originate, at least in part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measure reversion of malignant cells into phenotypically nonmalignant cells in 3D gels, we identified FAM83A as a candidate cancer-associated gene capable of conferring resistance to EGFR-TKIs. FAM83A overexpression in cancer cells increased proliferation and invasion and imparted EGFR-TKI resistance both in cultured cells and in animals. Tumor cells that survived EGFR-TKI treatment in vivo had upregulated FAM83A levels. Additionally, FAM83A overexpression dramatically increased the number and size of transformed foci in cultured cells and anchorage-independent growth in soft agar. Conversely, FAM83A depletion in cancer cells caused reversion of the malignant phenotype, delayed tumor growth in mice, and rendered cells more sensitive to EGFR-TKI. Analyses of published clinical data revealed a correlation between high FAM83A expression and breast cancer patients' poor prognosis. We found that FAM83A interacted with and caused phosphorylation of c-RAF and PI3K p85, upstream of MAPK and downstream of EGFR. These data provide an additional mechanism by which tumor cells can become EGFR-TKI resistant.