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Open AccessArticle

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

1
Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, 20133 Milan, Italy
2
Biochemistry Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
3
Cancer Genomics Laboratory, National Institute of Genomic Medicine, Mexico City 14610, Mexico
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(8), 2261; https://doi.org/10.3390/cancers12082261
Received: 9 July 2020 / Revised: 8 August 2020 / Accepted: 9 August 2020 / Published: 12 August 2020
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. View Full-Text
Keywords: microRNAs; triple-negative breast cancer; cisplatin; drug response microRNAs; triple-negative breast cancer; cisplatin; drug response
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Cataldo, A.; Romero-Cordoba, S.; Plantamura, I.; Cosentino, G.; Hidalgo-Miranda, A.; Tagliabue, E.; Iorio, M.V. MiR-302b as a Combinatorial Therapeutic Approach to Improve Cisplatin Chemotherapy Efficacy in Human Triple-Negative Breast Cancer. Cancers 2020, 12, 2261.

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