ERRF sensitizes ERBB2-positive breast cancer cells to lapatinib treatment likely by attenuating MCL1 and ERBB2 expression
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Leilei Qi1, Baotong Zhang2, Shiying Zhang1, Xinpei Ci1, Qiao Wu1, Gui Ma1, Ang Luo1, Liya Fu1, Jamie L. King2, Rita Nahta3, Jin-Tang Dong1,2
1Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
2Emory Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
3Emory Winship Cancer Institute, Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
Jin-Tang Dong, email: firstname.lastname@example.org
Keywords: ERRF, lapatinib, ERBB2, breast cancer, drug resistance
Received: December 28, 2016 Accepted: March 14, 2017 Published: March 21, 2017
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.
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