RANK-C Expression Sensitizes ER-Negative, EGFR-Positive Breast Cancer Cells to EGFR-Tyrosine Kinase Inhibitors (TKIs)

Background: We have previously shown that overexpression of RANK-c in ER-negative breast cancer cell lines attenuates aggressive properties of cancer cells, partially through a RANK-c/EGFR interaction. EGFR inhibition through TKIs in breast cancer has been tested in triple-negative disease settings with limited clinical benefit for patients. Here we test if expression of RANK-c in ER-negative breast cancer cells in conjunction with treatment with TK inhibitors (erlotinib or gefitinib) can affect survival and colony-forming capacity of cancer cells. Methods: Stably expressingMDA-MB-231-RANKc and SKBR3-RANK-c cells were employed to test proliferation and colony formation in the presence of TKIs. In addition, Western blot analysis was performed to dissect EGFR related signaling cascades upon TK inhibition in the presence of RANK-c. Results: Interestingly the two RANK-c expressing, ER-negative cells lines presented with a distinct phenotype concerning TKI sensitivity upon treatment. MDA-MB-231-RANK-c cells had a higher sensitivity upon gefitinib treatment, while erlotinib decreased the proliferation rate of SKBR3-RANK-c cells. Further, colony formation assays for MDA-MB-231RANK-c cells showed a decrease in the number and size of colonies developed in the presence of erlotinib. In addition, RANK-c seems to alter signaling through EGFR after TKI treatment in a cell type-specific manner. Conclusions: Our results indicate that ER-negative breast cancer cells that express RANK-c alter their sensitivity profile against tyrosine kinase inhibitors (erlotinib and gefitinib) in a cell type-specific and culture substrate-dependent manner.