Dynamic surveillance of tamoxifen-resistance in ER-positive breast cancer by CAIX-targeted ultrasound imaging

Tamoxifen-based hormone therapy is central for the treatment of estrogen receptor positive (ER⁺) breast cancer. However, the acquired tamoxifen resistance, typically co-exists with hypoxia, remains a major challenge. We aimed to develop a non-invasive, targeted ultrasound imaging approach to dynamically monitory of tamoxifen resistance. After we assessed acquired tamoxifen resistance in 235 breast cancer patients and a list of breast cancer cell lines, we developed poly(lactic-co-glycolic acid)-poly(ethylene glycol)-carbonic anhydrase IX mono antibody nanobubbles (PLGA-PEG-mAb_CAIX NBs) to detect hypoxic breast cancer cells upon exposure of tamoxifen in nude mice. We demonstrate that carbonic anhydrase IX (CAIX) expression is associated with breast cancer local recurrence and tamoxifen resistance both in clinical and cellular models. We find that CAIX overexpression increases tamoxifen tolerance in MCF-7 cells and predicts early tamoxifen resistance along with an oscillating pattern in intracellular ATP level in vitro. PLGA-PEG-mAb_CAIX NBs are able to dynamically detect tamoxifen-induced hypoxia and tamoxifen resistance in vivo. CAIX-conjugated NBs with noninvasive ultrasound imaging is powerful for dynamically monitoring hypoxic microenvironment in ER⁺ breast cancer with tamoxifen resistance.