Abstract
Abstract MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been implicated in cancer. Our research focuses on the miRNA mir-4728, which is located in an intron in the HER2 locus. The HER2 locus is amplified in approximately 15% of all breast tumors and is associated with a poor prognosis. Current therapeutic strategies for HER2-positive tumors involve targeted inhibition of the HER2 protein with monoclonal antibodies such as trastuzumab in combination with chemotherapy and surgery. However, if mir-4728 has a function independent of its host gene, targeting the HER2 protein alone may be insufficient. To investigate the role of mir-4728, we utilized antisense oligonucleotides to specifically block mir-4728 in a HER2-amplified breast cancer cell line, while leaving the protein receptor in tact. Polysome fractionation and ribosome profiling revealed that blocking the miRNA resulted in a substantial change in protein translation. We hypothesize that this effect may come as a result of mir-4728 being an indirect regulator of EIF4A, a key factor in the initiation of translation. In addition, we have observed changes in the synthesis of aromatase, a crucial enzyme in estrogen synthesis. These findings suggest that mir-4728 may play a role in the regulation of multiple pathways that contribute to cancer progression. Further investigation into this mechanism may provide valuable insight into the development of new therapeutic strategies for cancer treatment. Citation Format: Völundur Hafstad, Euisuk Han, Helena Persson. The impact of mir-4728 on translation and pathway regulation in HER2-amplified breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B002.
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