ERRF sensitizes ERBB2-positive breast cancer cells to lapatinib treatment likely by attenuating MCL1 and ERBB2 expression.
ERRF sensitizes ERBB2-positive breast cancer cells to lapatinib treatment likely by attenuating MCL1 and ERBB2 expression.
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ERRF 可能通过减弱 MCL1 和 ERBB2 表达而使 ERBB2 阳性乳腺癌细胞对拉帕替尼治疗敏感
DOI：
10.18632/oncotarget.16425
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发表时间：
2017-05-30
期刊：
影响因子：
--
通讯作者：
Dong JT
中科院分区：
文献类型：
--
作者：
Qi L;Zhang B;Zhang S;Ci X;Wu Q;Ma G;Luo A;Fu L;King JL;Nahta R;Dong JT
前期我们发现雌激素受体(ER)相关因子ERRF调节细胞增殖和肿瘤生长，其表达与乳腺癌ER状态和较好的生存期呈正相关，而与ERBB2(又称HER2)状态呈负相关。在这里，我们报告ERRF在ERBB2阳性的乳腺癌细胞对拉帕替尼的反应中也扮演着重要的角色，拉帕替尼是一种双重酪氨酸激酶抑制剂，可以阻断ERBB2和EGFR途径。在ERBB2阳性的乳腺癌细胞系中，ERRF的低水平表达与拉帕替尼耐药相关，耐药细胞系JIMT-1和MDA-MB-453的ERRF表达恢复增强了其对拉帕替尼的反应，而在对拉帕替尼敏感的细胞系BT-474和SK-BR-3中，ERRF的下调导致了拉帕替尼的耐药。ERRF增强的拉帕替尼敏感性在JIMT-1细胞的异种移植瘤中也得到证实。在ERBB2阳性乳腺癌患者中，较高水平的ERRF表达与对拉帕替尼的病理完全应答(PCR)和较好的生存相关。机制上，耐药细胞中ERRF的表达通过抑制MCL1和ERBB2的表达促进了拉帕替尼诱导的细胞凋亡。这些结果表明ERRF在ERBB2阳性乳腺癌的拉帕替尼反应中起重要作用，进一步研究ERRF可能有助于提高对拉帕替尼反应的预测性和敏感性。
Previously we found that the estrogen receptor (ER) related factor ERRF regulates cell proliferation and tumor growth, and its expression is positively associated with ER status and better survival but inversely associated with ERBB2 (also named HER2) status in breast cancer. Here we report that ERRF also plays an important role in the response of ERBB2-positive breast cancer cells to lapatinib, a dual tyrosine kinase inhibitor that interrupts the ERBB2 and EGFR pathway. In ERBB2-positive breast cancer cell lines, lower levels of ERRF expression correlated with lapatinib resistance, restoration of ERRF expression in lapatinib-resistant cell lines JIMT-1 and MDA-MB-453 enhanced their lapatinib responses, and knockdown of ERRF in lapatinib sensitive cell lines BT-474 and SK-BR-3 caused lapatinib resistance. ERRF-enhanced lapatinib sensitivity was also confirmed in xenograft tumors of JIMT-1 cells. In patients with ERBB2-positive breast cancer, higher level of ERRF expression correlated with both pathologic complete response (pCR) to lapatinib and better survival. Mechanistically, ERRF expression in resistant cells promoted lapatinib-induced apoptosis by attenuating MCL1 and ERBB2 expression. These results suggest that ERRF plays an important role in lapatinib response of ERBB2-positive breast cancer, and further study of ERRF could lead to improved prediction and sensitivity of lapatinib response.