Breast cancer (BC) is the most diagnosed cancer among women and second leading cause of cancer death among women. BC patients diagnosed with locally advanced or aggressive early stage (I-III) breast cancer receive systemic neoadjuvant chemotherapy (NAC) to downstage the breast tumor and avoid metastases to the axillary lymph node. Apart from patients with HER2+ tumors (~25%), use of Anthracycline, Cyclophosphamide and a Taxane (AC-T) based NAC regimen has become standard of care. However, response to ACT NAC is poor with majority of patients showing partial or no response with residual or whole tumor present at resection. Thus, accurate evaluations of the response to NAC will provide important information on the effect of systemic NAC, to guide improved therapy and reduce unwarranted side effects. Accordingly, cancer-extracellular vesicles (C-EVs) represent an emerging liquid biopsy modality for therapeutic response monitoring and outcome prediction. In this study, C-EVs isolated from blood plasma of BC patients prior to receiving NAC are characterized by their physicochemical properties such as size, concentration, and zeta-potential. Global protein profiling of isolated C-EVs was conducted using quantitative LC-MS/MS. Proteomic analysis identified eight proteins enriched in C-EVs from BC patients that did not respond to NAC compared to those who responded. Five out of the eight proteins were validated by western blot and classified as differentially present proteins. Functionally, the C-EVs from BC patients that did not respond to NAC increased luminal A BC MCF7 and triple negative BC MDA-MB-231 cell viability. Altogether, our findings suggest that when properly isolated, blood plasma C-EVs and the five proteins may be established as predictors of chemoresistance, and thus serve to identify patients that may not respond to treatment to spare them the toxic effects of NAC.
NIH R01 DA050169; At Stony Brook University - Molecular and Cellular Pharmacology PhD program, Scholars in Biomedical Sciences T32GM127253, Cancer Center, Proteomics Core, CIE IMSD-MERGE.
