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

Sci Rep. 2019 Nov 8;9(1):16383. doi: 10.1038/s41598-019-52797-z.


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.

MeSH terms

  • Ado-Trastuzumab Emtansine / pharmacology*
  • Antineoplastic Agents, Immunological / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Integrin alpha5beta1 / antagonists & inhibitors
  • Integrin alpha5beta1 / genetics
  • Integrin alpha5beta1 / metabolism
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-2 / metabolism


  • Antineoplastic Agents, Immunological
  • Integrin alpha5beta1
  • Multidrug Resistance-Associated Proteins
  • RNA, Small Interfering
  • Doxorubicin
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Ado-Trastuzumab Emtansine
  • multidrug resistance-associated protein 1