(72b) Fluid Shear Stress Causes Resistance to Chemotherapy Drugs in Breast Cancer

Over 90% of cancer deaths occur due to cancer metastasis. Metastasis is challenging to treat due to the general lack of specified treatment and detection. Metastatic tumors is typically only detected once the secondary tumor has already grown to a palpable size. Emerging technology is starting to facilitate liquid biopsy of blood samples for an earlier detection of metastatic cells known as circulating tumor cells (CTCs). Developing treatments that target CTCs, however, is challenging as current in vitro high-throughput drug screening methods rely on cells cultured in static conditions that do not experience fluid shear stress (FSS) as CTCs do in vivo. Furthermore, there is emerging evidence that CTCs behave like cancer stem cells (CSCs) and are resistant to existing chemotherapy. Therefore in this project, we developed an in vitro model to test for CTC drug sensitivity and have focused on elucidating how FSS affects the drug sensitivity of CTCs. We found that MCF7 breast cancer cells undergoing FSS were more resistant to both paclitaxel (PTX) and doxorubicin (DOX) than the statically cultured MCF7 cells (i.e., IC₅₀ of 90 nM vs. 3.5 µM, respectively for DOX). CD44⁺/CD24^- CSC subpopulation was also found to be increased in MCF7 FSS, FSS+PTX, and FSS+DOX treated cells. There was also a correlated increased gene expression of MDR1, MRP1, and BCRP drug resistance genes. FSS, FSS+PTX, and FSS+DOX further increased stemness-like characteristics in the MCF7 cell line. Interestingly, drug alone (static conditions) or FSS alone (no drug) did not increase drug resistance. These results suggest that there may be a synergistic effect of drug resistance for cancer cells under FSS, which may impact how drugs should be administered in the future for the treatment of CTCs and metastatic cancers.