Targeting tumor microenvironment of metastatic triple negative breast cancer cells via exosomes derived from non-invasive breast cancer cells for multi-drug resistance inhibition and enhancing drug susceptibility

The current challenging situation in the domain of oncology is to develop an effective targeted anti-cancer therapy for metastatic breast cancer. There is a lack of efficacious treatment for triple negative breast cancer (TNBC) due to the absence of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Several efforts are being made for the development of drugs, aiming the multifaceted chemoresistance nature of TNBC. In this study, we have targeted MDA MB-231, a TNBC cell line with exosomes derived from MCF-7, a non-invasive breast cancer (nBC) cell line, to modulate the tumor niche of the metastatic cells. There was ⁓1.6 fold increase in reactive oxygen species (ROS) generation and S-phase growth arrest in the cell cycle following treatment with the exosomes. Gene expression analysis exhibited that the exosome treatment resulted in the down regulation of the multi-drug resistance (MDR) receptors with ⁓0.7 fold decrease in breast cancer resistance protein (BCRP) expression along with the decrement in the expression of the epithelial-to-mesenchymal (EMT) markers like Vimentin and TWIST1 by ⁓0.7 and ⁓0.8, respectively. We could also observe increase in drug susceptibility in metastatic TNBC cell line following treatment with lapatinib, a tyrosine kinase inhibitor in combination with the exosomes. The current strategy makes the metastatic breast cancer cells, MDA MB-231 more susceptible to drugs, thereby resulting in effective anti-cancer therapy.