J. C. Sporn1, E. Katsuta1, L. Yan2, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Biostatistics & Bioinformatics,Buffalo, NY, USA
Introduction: MicroRNAs are short RNA molecules of about 18 to 24 nucleotides in length that target certain messenger RNAs (mRNAs) leading to its degradation and thereby preventing them from coding for a specific protein. MicroRNA-34a (miR-34a) was found to be lost or decreased in many different cancers, suggesting a role as a tumor suppressor, and re-expression of miR-34a has been investigated as a potential treatment of cancers in clinical trials. In breast cancer models, miR-34a was shown to be implicated in proliferation and cell differentiation and its expression was inhibited within the breast cancer stem cell pool. We were interested in the role of miR-34a in various breast cancer subtypes to further elucidate the context-specific role of miR-34a in cancer.
Methods: We utilized The Cancer Genome Atlas (TCGA) containing genetic and molecular data, clinical profiles and survival information for 985 breast cancers. Survival analysis was performed comparing a group with low expression of miR-34a to a group with high expression. Expression of miR-34a was compared based on clinicopathological parameters including ER and HER2 status. Gene Set Enrichment Analysis was performed for the miR-34a high and low groups.
Results: Patients with tumors with low expression of miR-34a have a better prognosis than patients with tumors with high expression of miR-34a (p=0.003). An identical association was found for the ER positive cohort where patients with tumors with low expression of miR-34a had an improved overall survival compared to patients with tumors with high expression of miR-34a (p<0.001). Interestingly, this effect was not only lost, but reversed in the ER negative cohort where high miR-34a expression was associated with improved disease-free survival compared to low miR-34a expression.
Conclusion: MiR-34a plays complex and even opposing roles in breast cancer. While we confirmed its classical role as a tumor suppressor in the ER negative cohort, we demonstrated an oncogenic role in ER positive cancers where high expression was associated with a worse prognosis.
