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

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.

• Authors: Alessandra Cataldo, Douglas G Cheung, Andrea Balsari, Elda Tagliabue, Vincenzo Coppola, Marilena V Iorio, Dario Palmieri, Carlo M Croce
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 1 Pg. 786-97 (Jan 05 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26623722 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• Antineoplastic Agents
• E2F1 Transcription Factor
• E2F1 protein, human
• MIRN302A microRNA, human
• MicroRNAs
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Caspase 3
• Caspase 7
• Cisplatin

Topics

• 3' Untranslated Regions (genetics)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Ataxia Telangiectasia Mutated Proteins (genetics)
• Breast Neoplasms (genetics, metabolism, pathology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Cell Survival (drug effects, genetics)
• Cisplatin (pharmacology)
• DNA Damage
• E2F1 Transcription Factor (genetics)
• Female
• Flow Cytometry
• HeLa Cells
• Humans
• MicroRNAs (genetics)
• Reverse Transcriptase Polymerase Chain Reaction