Cell proliferation and invasion are regulated differently by EGFR and MRP1 in T-DM1-resistant breast cancer cells

Yukinori Endo,Sarah Lyon,Nishant Mohan,Yi Shen,Wen Jin Wu

doi:10.1038/s41598-019-52797-z

Yukinori Endo, Sarah Lyon + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-52797-z

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Abstract

We recently reported that T-DM1-resistant JIMT1 (T-DM1R-JIMT1) cells exhibited high invasive activity via EGFR and integrin cooperated pathways and gained cross-resistance to doxorubicin. Here, we show that EGFR positively coordinates with MRP1 in T-DM1R-JIMT1 cells to contribute to cross-resistance to doxorubicin. Downregulating EGFR and MRP1 inhibits T-DM1R-JIMT1 cell growth and re-sensitizes T-DM1R cells to doxorubicin, suggesting that dual targeting EGFR and MRP1 could serve as a therapeutic approach to overcome T-DM1 resistance. However, it increases cell invasion activity of T-DM1R-JIMT1 cells with molecular and cellular phenotypes similar to the breast cancer cells that express low levels of HER2 (MDA-MB-231 and BT-549 cells). Importantly, the invasion activity of MDA-MB-231 and BT-549 cells is also significantly increased after chronically exposed to T-DM1 although cell growth of MDA-MB-231 and BT-549 cells is not inhibited by T-DM1. These results highlight the importance of HER2 heterogenicity in HER-positive breast cancers treated with T-DM1. Our study also provides evidence demonstrating that proliferation and invasion activities of T-DM1R-JIMT1, and MDA-MB-231 and BT-549 cells are regulated by different mechanisms and that different aspects of cancer cell behaviors affected by targeted-therapeutics should be fully characterized in order to overcome T-DM1-resistant disease and to prevent cancer metastasis.

Highlights

Ado-trastuzumab emtansine is an antibody-drug conjugate (ADC) for patients with HER2-positive metastatic breast cancer whose disease has progressed on trastuzumab plus chemotherapy[1]
Using JIMT1 cells, which have been commonly used as a cellular model to study the mechanisms of T-DM1 resistance[9,10], we previously showed that T-DM1-resistant JIMT1 cells acquired cross-resistance to chemotherapeutic drugs such as paclitaxel and doxorubicin (Dox)[10]
After T-DM1R cells were treated with both Dox and erlotinib, cell growth was significantly inhibited as compared with that of T-DM1R-JIMT1 cells treated with either Dox or erlotinib. These results indicate that the increased epidermal growth factor receptor (EGFR) activity is required for acquiring cross-resistance to Dox in T-DM1R-JIMT1 cells

Summary

Introduction

Ado-trastuzumab emtansine ( known as T-DM1) is an antibody-drug conjugate (ADC) for patients with HER2-positive metastatic breast cancer whose disease has progressed on trastuzumab plus chemotherapy[1]. These results indicate that the increased EGFR activity is required for acquiring cross-resistance to Dox in T-DM1R-JIMT1 cells.

Results

Conclusion