The Mechanism And Clinical Implication Of MicroRNA-27b In Breast Cancer Cells Proliferation And Chemoresistance

Chemotherapy is the cornerstone of systemic treatment of breast cancer,butthedevelopment of chemoresistance severely limits the therapeutic effect.The molecular mechanism of chemoresistance is complex and has not been fully elucidated.The development of chemoresistant reversal agents is slow.Previous studies have revealed that microRNAs(miRNAs)play an important regulatory role in breast cancer chemoresistance by regulating the expression of downstream target genes at the post-transcriptional level.TCGA is the largest database of cancer information.The miRNA expression profiles were compared in a large number of breast cancer tissues and normal tissues in TCGA.In addtion,breast cancer patients who have received paclitaxel chemotherapy are divided into chemo-resistant group and chemo-sensitive group according to their response.The miRNA expression profiles in breast cancer tissues of the two groups were also compared.A miRNA library was constructed including dysregulatedmiRNAs in the above two parts.Myeloid breast cancer is a special histo-type of triple-negative breast cancer with chemotherapy as the main treatment.There are few studies on chemoresistance of myeloid breast cancer.We focused on the resistance of paclitaxel in the multidrug-resistant breast cancer cell line,Bads-200,and found miR-27bcan decrease the resistance of Bads-200 to paclitaxel more effectively than other miRNAs in library.The results of clinical samples showed that miR-27b was significantly down-regulated in breast cancer tissues,and the expression was lower in patients relapsed after chemotherapy.Statistical analysis found that the low expression of miR-27b in breast cancer tissues is closely to disease progression and poor prognosis.The negative relationship of miR-27b and cell resistance degree to paclitaxel also indicated a close correlation of miR-27b and chemoresistance.The experiments invitro revealed that miR-27b could significantly inhibit the Proliferationof myeloid breast cancer cells and the resistance to variouschemotherapeutic drugs.The regulatory function of miR-27b was equally effective in other breast cancer cells.The experiments in vivo showed that miR-27b can significantly enhance the inhibitory effect of paclitaxel on the growth of myeloid-resistant cells and reduce its drug resistance.The potential target genes of miR-27b were predicted through bioinformatics technology,and screened in KEGG and GO databases.The outcomes showed association of potential targets with important signaling pathways such as tumorigenesis,drug responses.The results of dual-luciferase assays indicatedCBLB and GRB2 are direct targets of miR-27b.The following study demonstrated that miR-27b can inhibit cell proliferation and potentially reverse multi-chemoresistacne by down-regulating CBLB,GRB2.The down-regulated CBLB,GRB2 could further inactivate important proteins in the downstream of Akt,Erk signaling pathwaysand anti-apoptotic proteins,Bcl-2 and Bcl-xl,thereby inhibiting cell proliferation and promoting apoptosis.In summary,miR-27b may act as a predictive factor for prognosis and chemoresistance in breast cancer patients,and significantly inhibit the proliferation and drug resistance of breast cancer cells by down-regulating CBLB and GRB2.These findings will help us to deepen our understanding of the mechanisms of breast cancer chemotherapeutic resistance and provide potential targets for breast cancer treatment,new ideas for the development of chemotherapy sensitizers.