Abstract P4-07-10: Epithelial mesenchymal transition associated with high miR-221 and integrin β6 leads to poor prognosis in hormone receptor positive HER2 negative breast cancers

Abstract

Abstract Background: MicroRNA mediated molecular alterations are involved in the initiation and progression of cancer. Altered expression of multiple microRNAs is associated with endocrine resistance in hormone receptor positive HER2 negative (HR+/HER2-ve) cancer. The role of miR-221 in inducing epithelial to mesenchymal transition (EMT) is well documented especially in cell line model systems. However, the detailed mechanism of specific microRNAs in intrinsic and acquired resistance to endocrine therapy needs to be worked out. In addition, more needs to be done in the documentation of these mechanisms in human breast cancer specimens with complete clinical documentation and long-term follow-up. In this study, we have evaluated the clinical significance of miR-221 and its mechanistic role in EMT using human specimens and cell line models. Materials and Methods: Formalin fixed paraffin embedded tumor from 129 HR+/HER2-ve breast cancer patients with a median follow up of 63 months were used for estimation of miR-221 by quantitative real time PCR. Expression levels of genes which are direct targets of miR-221 and related genes in EMT were analysed from these tumors. Survival between miR-221 high and low groups was compared by Kaplan Meier survival curves and prognostic relevance was estimated by Cox proportional hazard model. Cell line experiments to investigate the role of miR-221 in inducing EMT through integrin β6 are underway in both wild type and tamoxifen resistant MCF-7 cell lines (A gift from Prof Ben Ho Park, Johns Hopkins University School of Medicine). Results: A significant elevated level of miR-221 was observed in small proportion (14%) of HR+/HER2-ve tumors. miR-221 expression had an inverse correlation with both ER protein and ESR1 mRNA levels within HR+/HER2-ve tumors. Tumors with high levels of miR-221 showed significantly higher expression of integrin β6 which is a robust marker of EMT. Patients with high expression of miR-221 had a poorer survival in Kaplan Meier analysis. Results of interrogation of EMT mediated through integrin related pathways involving miR-221 in cell line models will be presented. Discussion: The association between miR-221 and integrin β6 in HR+/HER2-ve breast cancer with endocrine resistance suggests a potential link between an epigenetic regulator and a mediator of tumor-stromal interaction. The other mediators involved in this pathway are being investigated. miR-221 could be potentially used as a marker for identification of a poor prognostic subtype within HR+/HER2-ve breast cancers. Citation Format: Prabhu JS, Kaul R, Korlimarla A, Desai K, Gangadharan C, Rajarajan S, Nair MG, Alexander A, Kaluve R, Manjunath S, Correa M, Prasad MSN, Patil S, Srinath BS, Sridhar TS. Epithelial mesenchymal transition associated with high miR-221 and integrin β6 leads to poor prognosis in hormone receptor positive HER2 negative breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-07-10.