MiR-302b as a Combinatorial Therapeutic Approach to Improve Cisplatin Chemotherapy Efficacy in Human Triple Negative Breast Cancer

ABSTRACT: Chemotherapy is still the standard–of-care for triple-negative breast cancers (TNBCs). Here, we investigated miR-302b as therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Material and method: TNBC xenografted mice were treated with miR-302b or control, alone or with cisplatin. Genome-wide transcriptome analysis and independent-validation of ITGA6 expression was assessed on mice tumor samples. SiRNA-knockdown of ITGA6 was performed to evaluate cisplatin response in vitro. Further, potential transcription factors of ITGA6 (E2F1, E2F2 and YY1) were explored to define the miRNA molecular mechanism. MiR-302b expression was also assessed in TNBC patients treated with chemotherapy. Results: MiR-302b-cisplatin combination significantly impaired tumor growth versus control, through indirect ITGA6 downregulation. Indeed, ITGA6 was downmodulated in mice treated with miR-302b-cisplatin and ITGA6 silencing increased drug sensitivity in TNBC cells. In silico analyses and preclinical assays pointed out the regulatory role of E2F family and YY1 on ITGA6 expression under miR-302b-cisplatin treatment. Finally, miR-302b enrichment correlates with better overall survival in 118 TNBC patients. Conclusion: MiR-302b can be exploited as a new therapeutic tool to improve the response to chemotherapy, modulating E2F family, YY1 and ITGA6 expression. Moreover, miR-302b could be defined as new prognostic factor in TNBC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152322 | GEO | 2020/08/21

REPOSITORIES: GEO