Abstract
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.
Highlights
The ERBB2-positive subtype of breast cancer is characterized by gene amplification or protein overexpression of ERBB2, a member of the human epidermal growth factor receptor family
Lapatinib resistant clones had been developed from both SK-BR-3 and BT474 cell lines [44], and analysis of available genomewide expression data for these resistant cells in the Gene Expression Omnibus (GEO) database [44] indicates that ERRF mRNA expression was dramatically downregulated in the lapatinib resistant clones of SK-BR-3 and BT-474 cells (Figure 1D)
Considering that ERRF enhances lapatinibinduced apoptosis (Figure 5), ERRF expression inversely correlates with ERBB2 status [41], and MCL1 is an anti-apoptotic gene that mediates lapatinib resistance in HCT116 cells [50] and an upstream regulator of ERBB2 [51], we evaluated whether ERBB2 and MCL1 are related to ERRF in any way in breast cancer cells
Summary
The ERBB2-positive subtype of breast cancer is characterized by gene amplification or protein overexpression of ERBB2, a member of the human epidermal growth factor receptor family. ERBB2 protein is an important marker and therapeutic target for about 30% of breast cancer patients, and such patients tend to have a shorter disease free survival and overall survival [1,2,3,4,5,6]. The luminal B subtype cancers are treated with endocrine therapies in combination with. One of the targeted therapies is the Lapatinib, a dual tyrosine kinase inhibitor that interrupts the ERBB2 and EGFR pathway in the treatment of ERBB2 positive breast cancer, which is used as ditosylate and orally active [22]. Lapatinib is primarily used in patients with advanced-stage, ERBB2positive breast cancer that has stopped responding to anthracyclines, taxanes, and herceptin [19, 23]
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