Abstract
Introduction: Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs). Here, we investigated miR-302b as a therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Materials and Methods: TNBC-xenografted mice were treated with miR-302b or control, alone or with cisplatin. Genome-wide transcriptome analysis and independent-validation of Integrin Subunit Alpha 6 (ITGA6) expression was assessed on mice tumor samples. Silencing of ITGA6 was performed to evaluate cisplatin response in vitro. Further, potential transcription factors of ITGA6 (E2F transcription facor 1 (E2F1), E2F transcription factor 2 (E2F2), and Yin Yang 1 (YY1)) were explored to define the miRNA molecular mechanism. The miR-302b expression was also assessed in TNBC patients treated with chemotherapy. Results: The miR–302b-cisplatin combination significantly impaired tumor growth versus the 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 the E2F family and YY1 on ITGA6 expression under miR-302b–cisplatin treatment. Finally, miR-302b enrichment correlated 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 the E2F family, YY1, and ITGA6 expression. Moreover, miR-302b could be defined as a new prognostic factor in TNBC patients.
Highlights
Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs)
To explore the plausibility of miR-302b miRNA-based therapy in combination with cisplatin to treat TNBC, MDA-MB-231 TNBC cells were orthotopically injected into the mammary fat pad of female Severe Combined Immunodeficient (SCID) mice
These results suggest that the combinatorial effect of miR-302b and cisplatin on TNBC cell viability is exerted thought a mechanism involving the E2F family, Yin Yang 1 (YY1) and Integrin Subunit Alpha 6 (ITGA6), all molecules modulated by cisplatin activity and implicated in the response to this drug
Summary
Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs). We investigated miR-302b as a therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Materials and Methods: TNBC-xenografted mice were treated with miR-302b or control, alone or with cisplatin. Potential transcription factors of ITGA6 (E2F transcription facor 1 (E2F1), E2F transcription factor 2 (E2F2), and Yin Yang 1 (YY1)) were explored to define the miRNA molecular mechanism. MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs (19–22 nt) that play key roles in different biological processes including cancer [1]. MicroRNAs are able to regulate mechanisms of resistance to chemotherapy such as DNA repair, cell cycle regulation, and escape from apoptotic pathways [4]. Intrinsic or acquired chemotherapy resistance is a relevant feature in Cancers 2020, 12, 2261; doi:10.3390/cancers12082261 www.mdpi.com/journal/cancers
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