Functional Analysis and Therapeutic Potential of miR-708 in Metastatic Breast Cancer
Technical Report,30 Sep 2013,29 Sep 2017
Joan and Sanford I. Weill Medical College of Cornell University New York United States
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Over 200,000 new cases of invasive breast cancer are diagnosed in the United States each year and account for approximately 40,000 deaths. From a treatment perspective, breast cancer is a paradigm for individualized medicine with two personalized therapies in use endocrine therapy for hormone receptor positive patients and HER2-targeted agents such as trastuzumab for HER2 patients. However, patients with TNBC basal-like subtype lacking all three receptors ER, PR and Her2neu are refractory to these therapies. Surgical resection and standard chemotherapy regimens remain the only therapeutic options for women with TNBC, and these treatments usually fail resulting in an aggressive metastatic relapse and short overall survival. Therefore, there is an urgent need to develop new targeted therapeutic approaches. This proposal provides a mechanism-based approach, which promises to impact the treatment of TNBC, a subtype of highly metastatic breast cancer that confers the worst outcome. We have identified miR-708 as a potential metastasis suppressor in breast cancer. miR-708 targets neuronatin to decrease intracellular calcium level, which inactivates ERKFAK pathways to impair cell migration and metastases. Analysis of miR-708 upstream regions showed enrichment of PRC2 which was associated with elevated H3-K27me3 levels. We hypothesize that PRC2-induced H3-K27me3 silences miR-708 in metastasis. Significantly, systemic delivery of synthetic miR-708 blocked TNBC metastases, providing a rationale for developing miR-708 as a novel therapeutic agent against metastatic breast cancer. Our objective is to dissect the epigenetic regulation of miR-708, so that epigenetic therapies can be considered for metastatic breast cancer, and evaluate the therapeutic efficacy of synthetic miR-708. Dissecting the epigenetic regulation of miR-708 will generate translational opportunities for patients with TNBC.
- Medicine and Medical Research