Abstract 4033: MiR-21 upregulation in breast cancer cells leads to PTEN loss and Herceptin resistance

Abstract

Abstract MicroRNAs (miRNA) are a class of small 22-nucleotides endogenous non-coding RNAs which serve as regulators of gene expression by targeting specific messenger RNAs (mRNA). Aberrant expression of certain microRNAs can lead to therapeutic drug resistance, such as Cisplatin resistance by miR-214 targeting PTEN. Our lab previously found that PTEN loss confers Herceptin resistance in ErbB2-overexpressing breast cancers. Other studies in hepatocellular carcinoma have shown that miR-21 targets the 3′UTR of PTEN mRNA leading to downregulation of PTEN protein levels. Based on these findings, we hypothesized that overexpression of miR-21 may confer Herceptin resistance in breast cancer patients by downregulation of PTEN. To test this hypothesis, mir-21 and/or control miRNA were transiently transfected and expressed in ErbB2-overexpressing AU565 and SKBr3 breast cancer cell lines, followed by Herceptin treatment. We found that cells with increased miR-21 had reduced PTEN expression and were significantly more resistant to Herceptin treatment versus control miRNA transfected cells. Conversely, when we knocked down miR-21 in high ErbB2 expressing BT474 cells, the cells showed increased PTEN expression and became more sensitive to Herceptin treatment versus control miRNA transfected cells. To determine the clinical relevance of our findings, we detected miR-21 level in patients’ breast cancers with ErbB2 expression that were treated with Herceptin and we found that high miR-21 level significantly correlated with patients’ poor response to Herceptin treatment and disease progression. We are currently identifying other targets of miR-21 to better understand the mechanisms of miR-21 mediated-Herceptin resistance, which may provide new insight on how to overcome Herceptin resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4033.