Ultrasound reverses chemoresistance in breast cancer stem cell like cells by altering ABCG2 expression

Abstract

Doxorubicin (DOX) resistance in breast cancer largely results from the breast cancer stem cell like cells (BCSCs) which could be targetted to improve the efficacy of chemotherapy. Cell permeabilization using microbubbles (MBs) and ultrasound (US) have the potential for delivering molecules into the cytoplasm. We aim to evaluate a new methodology of US on BCSCs. First, our findings indicated that ALDHA1⁺ spheres which were derived from fresh primary breast cancer samples displayed stem cell like features and were resistant to DOX. In patient cohort, we revealed the presence of a variable fraction of ALDHA1⁺cells in nine out of ten. We, for the first time, showed a new US-MB treatment condition which could be used on ALDHA1⁺ BCSCs by fluorescence measurement and calcein assay. Next, we demonstrated the efficacy of combined treatment on human BCSCs in vitro and in vivo using DOX and US-MB: the combined treatment with much reduced drug dosage significantly suppressed the stem cell like features of BCSCs and induced BCSCs apoptosis. Furthermore, we suggested that decreased ABCG2 level might be one of the mechanisms by which US-MB medicated DOX treatment. In conclusion, this new US-MB treatment condition has clinical potential in breast cancer therapy by targetting BCSCs; thereby holding benefits for breast cancer patients.