Cryptotanshinone Breaks ERα-dependent and -independent BCRP Dimerization to Reverse the Multidrug Resistance in Breast Cancer

Abstract Background: Not only a long-term anti-estrogen therapy, but also estrogen receptor-negative breast cancer are generally prone to induce resistance, causing poor prognosis in clinic. Breast cancer resistance protein (BCRP) plays an important role in multidrug resistance. Here it is to elucidate the mechanism that a natural compound cryptotanshinone inhibits BCRP.Methods: HPLC was for analyzing the special compound concentration and molecular docking assay for the affinity of compound with protein. Non-reducing gradient gel electrophoresis and fluorescence resonance energy transfer (FRET) microscopy imaging were used to detect polymer and stain the membrane protein. Immunofluorescence staining, plasmids transfection, real-time PCR and western blot were also used.Results: Cryptotanshinone, an anti-estrogen compound was firstly found to inhibit breast cancer resistance protein (BCRP) membrane dimerization to attenuate its transport function. And this process is dependent on estrogen receptor α (ERα) in breast cancer. Furthermore, the resistant breast cancer cells with high BCRP expression are also sensitive to cryptotanshinone because it can bind to BCRP and significantly inhibit membrane dimer of BCRP although they are ERα-negative, suggesting that BCRP expression is essential to cryptotanshinone reversing the resistance; Meanwhile, the combination of cryptotanshinone and chemotherapy drugs could obviously enhance the chemotherapeutic effect. Conclusion: Cryptotanshinone is a novel natural BCRP inhibitor via blocking the formation of BCRP membrane dimer by an ERα-dependent and -independent way. Cryptotanshinone reverses resistance dependent on BCRP in breast cancer.