Abstract
Abstract The identification of minimally-invasive biomarkers, in efforts to aid in patient-tailored disease management, has become a key focus of cancer research. Recent studies by ourselves and others have reported the existence of circulating miRNAs associated with breast cancer. Despite this progress, resistance to anti-cancer treatment remains a major obstacle in the treatment of this disease and unfortunately there are no reliable methods of predicting sensitivity/resistance to anti-cancer agents. This study aimed both to (i) identify miRNAs differentially-expressed in the breast cancer cell line SKBR3 and its Trastuzumab-resistant variant, SKBR3-H, developed by exposure to Trastuzumab for 6 months; and to (ii) investigate if corresponding differential levels of miRNAs were detectable in conditioned media (CM) from these cells, reflecting the relative sensitive/resistance profile of the SKBR3-H comparing to age-matched control SKBR3 cells. Global analysis of miRNAs was successfully performed on biological triplicate RNA specimens isolated from SKBR3 cells, SKBR3-H cells and on their respective CM, using TaqMan low density arrays representing 667 human miRNAs. 71.5% (477/667) miRNAs were detected in SKBR3; most (85%; 406/477) of which were detected in its CM. For SKBR3-H, 75.7% (505/667) miRNA analyzed were present in the cells, with 70% (354/505) of these also detected in corresponding CM. Of the 187 miRNAs up-regulated by at least 2-fold in SKBR3-H compared to SKBR3 cells, 6.42% (12/187) were up-regulated in corresponding CM. Of the 62 miRNAs down-regulated by at least 2 fold in SKBR3-H compared to SKBR3 cells, more than half (53.2%; 33/62) were down-regulated in corresponding CM. Several differentially regulated miRNAs were selected from TLDA results and subsequently validated in triplicate by qRT-PCR. Overall, the many hundred (∼500) miRNAs detected in CM further supports the existence of extracellular miRNAs and so their potential as minimally-invasive biomarkers. Furthermore, we identified a number of miRNAs that may help predict response to Trastuzumab. Our current research involves investigating the relative expression of miRNAs in SKBR3 variants resistant to other HER2-targeted agents and also examining the potential target genes for miRNAs identified as of most relevance here. Exploring the occurrence of these miRNAs in relevant patients’ serum specimens is now warranted to investigate clinical application. Acknowledgements: Science Foundation Ireland's SRC award to MTCI (08/SRC/B1410). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4938. doi:10.1158/1538-7445.AM2011-4938
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