Breast cancer resistance protein (BCRP)-containing circulating microvesicles contribute to chemoresistance in breast cancer

Abstract

Abstract. At present, one of the major problems of cancer therapy is drug resistance. Breast cancer resistance protein (BCRP), a marker of the multidrug-resistant phenotype, affects drug absorption, distribution, metabolism, and excretion in normal tissues. Meanwhile, extracellular vesicles (EVs) have attracted increasing attention as a medium of cell-to-cell communication. However, the association between BCRP and circulating EVs remains unclear. The present study demonstrated that patients who did not respond or had progressive/ stable disease following chemotherapy had markedly higher BCRP levels compared to those that did not receive chemotherapy. Moreover, BCRP was upregulated at the mRNA and protein levels in tumor-derived circulating EVs from patients with a poor response to chemotherapy. Interestingly, the results also demonstrated that BCRP was co-expressed with MUC1, which is frequently expressed in breast cancer and is exported via EVs, and both BCRP and MUC1 were up-regulated after chemotherapy. In conclusion, the present study indicates that tumor-derived circulating EVs that carry BCRP may serve as a predictive biomarker of the response to chemotherapy for breast cancer. In addition, the results provide a window for individualized treatment to overcome resistance to chemotherapeutic drugs.

Extracellular vesicles swarm the cancer microenvironment: from tumor–stroma communication to drug intervention

“…In the context of the neo-adjuvant treatment of breast carcinoma, elevated levels of the EV-bound MDR-glycoprotein BCRP were detected in non-responders compared to responders or treatment naïve patients 14 . In addition, the receptor channel protein TRCP5, a known regulator of multidrug resistance glycoprotein-P, was required for EV formation in Studying EV-based therapies, some groups have explored the utilization of EVs as therapeutic delivery systems.…”

Monitoring Therapy Efficiency in Cancer through Extracellular Vesicles

“…BCRP was found to be upregulated at the mRNA and protein levels in circulating EVs from cancer patients that had a poor response to chemotherapy. They also found that BCRP and flotillin-2 were upregulated in tumor samples from nonresponsive patients [30]. Flotillin-2 has been shown to be involved in various cellular processes such as cell adhesion and signal transduction through receptor tyrosine kinases as well as in cellular trafficking pathways [31].…”

“…Chen et al [30] (Table 1) analyzed the relationship between breast cancer resistance protein (BCRP) and circulating EVs (microvesicles). The group showed that the levels of BCRP in patients who did not respond or had progressive/stable disease following chemotherapy were higher compared to those that did not receive chemotherapy.…”

“…Nevertheless, these markers did not accurately estimate patient response and lacked sensitivity revealing the need for improved markers. Tumor-derived circulating EVs that carry BCRP might provide a predictive biomarker for the response to chemotherapy of breast cancer [30].…”

The biological and clinical significance of stromal-epithelial interactions in breast cancer

“…EVs can reprogram cancer cell metabolism, mediate therapeutic drug interactions, and are implicated in driving the transformation of fibroblasts and other TME cells to a CAF phenotype. [61][62][63] EVs can in turn enhance the metastatic potential of the tumour such as up-regulating MMP-9 expression in melanoma cells and reprogramming cancer cells with enhanced metastatic potential. 64 Le et al 65 showed that EVs containing miR-200 can alter gene programming and promote MET.…”