Oncotarget

Research Papers:

miR-302b enhances breast cancer cell sensitivity to cisplatin by regulating E2F1 and the cellular DNA damage response

Alessandra Cataldo, Douglas G. Cheung, Andrea Balsari, Elda Tagliabue, Vincenzo Coppola, Marilena V. Iorio, Dario Palmieri, Carlo M. Croce _

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Oncotarget. 2016; 7:786-797. https://doi.org/10.18632/oncotarget.6381

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Abstract

Alessandra Cataldo1,2, Douglas G. Cheung1, Andrea Balsari2,3, Elda Tagliabue3, Vincenzo Coppola1, Marilena V. Iorio4, Dario Palmieri1 and Carlo M. Croce1

1 Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine and Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

2 Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

3 Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy

4 Start Up Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy

Correspondence to:

Carlo M. Croce, email:

Dario Palmieri, email:

Keywords: breast cancer, miR-302b, cisplatin, E2F1, ATM, DDR

Received: October 29, 2015 Accepted: November 10, 2015 Published: November 25, 2015

Abstract

The identification of the molecular mechanisms involved in the establishment of the resistant phenotype represents a critical need for the development of new strategies to prevent or overcome cancer resistance to anti-neoplastic treatments.

Breast cancer is the leading cause of cancer-related deaths in women, and resistance to chemotherapy negatively affects patient outcomes. Here, we investigated the potential role of miR-302b in the modulation of breast cancer cell resistance to cisplatin.

miR-302b overexpression enhances sensitivity to cisplatin in breast cancer cell lines, reducing cell viability and proliferation in response to the treatment. We also identified E2F1, a master regulator of the G1/S transition, as a direct target gene of miR-302b. E2F1 transcriptionally activates ATM, the main cellular sensor of DNA damage. Through the negative regulation of E2F1, miR-302b indirectly affects ATM expression, abrogating cell-cycle progression upon cisplatin treatment. Moreover miR-302b, impairs the ability of breast cancer cells to repair damaged DNA, enhancing apoptosis activation following cisplatin treatment.

These findings indicate that miR-302b plays a relevant role in breast cancer cell response to cisplatin through the modulation of the E2F1/ATM axis, representing a valid candidate as therapeutic tool to overcome chemotherapy resistance.


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