Cataldo Alessandra, Cheung Douglas G, Balsari Andrea, Tagliabue Elda, Coppola Vincenzo, Iorio Marilena V, Palmieri Dario, Croce Carlo M
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.
Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
Oncotarget. 2016 Jan 5;7(1):786-97. doi: 10.18632/oncotarget.6381.
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.
确定参与耐药表型形成的分子机制是开发预防或克服癌症对抗肿瘤治疗耐药性新策略的关键需求。乳腺癌是女性癌症相关死亡的主要原因，对化疗的耐药性会对患者预后产生负面影响。在此，我们研究了miR-302b在调节乳腺癌细胞对顺铂耐药性中的潜在作用。miR-302b的过表达增强了乳腺癌细胞系对顺铂的敏感性，降低了对该治疗的细胞活力和增殖能力。我们还确定E2F1（G1/S期转换的主要调节因子）是miR-302b的直接靶基因。E2F1转录激活DNA损伤的主要细胞传感器ATM。通过对E2F1的负调控，miR-302b间接影响ATM表达，在顺铂治疗后消除细胞周期进程。此外，miR-302b损害乳腺癌细胞修复受损DNA的能力，增强顺铂治疗后的凋亡激活。这些发现表明，miR-302b通过调节E2F1/ATM轴在乳腺癌细胞对顺铂的反应中发挥相关作用，是克服化疗耐药性的有效治疗工具候选者。
