Abstract 1912: Combinatorial targeting of PI3K and MAPK signaling pathways using microRNAs to inhibit tumor growth and metastasis in breast cancer

Abstract PI3K/Akt and MAPK signaling pathways, regulating cancer cell proliferation, apoptosis and metastasis, are among the top most deregulated pathways in cancer. Current kinase inhibitors used in clinics have limited success since one of these pathways gets activated when the other is suppressed. Alternatively, simultaneous silencing of both pathways results in high toxicity. Here, we aimed to establish a microRNA-based, non-toxic approach to inhibit these pathways simultaneously in breast cancer. By analyzing our previously published Reverse Phase Protein Array (RPPA) data showing differential expression of 26 proteins upon overexpression of 733 different miRNAs, we selected top miRNAs significantly deregulating PI3K and MAPK pathways as well as cell cycle. We narrowed down the list by selecting miRNAs whose predicted targets were among the PI3K and MAPK pathway elements. We came up with a tumor suppressor miRNA affecting both in vitro viability and migration/invasion of breast cancer cells. We identified the set of differentially expressed genes in breast cancer patients under low and high expression of the miRNA. A significant association was observed between the expression of the miRNA or its identified gene signature and clinico-pathological properties of breast cancer patients. Combinatorial knockdown of targets of the miRNA that are in PI3K and MAPK pathways as a cocktail phenocopied the tumor suppressive effects of the miRNA in breast cancer cell lines. Notably, low expression of the target cocktail predicts a better outcome in breast cancer patients. Overall, we identified a tumor suppressor miRNA to be used an alternative to current kinase inhibitor-based therapies for major subtypes of breast cancer by suppressing both PI3K and MAPK pathways and as a result inhibiting proliferation and migration/invasion in breast cancer. Citation Format: Merve Mutlu, Ozge Saatci, Erol Eyupoglu, Umar Raza, Ozgur Sahin. Combinatorial targeting of PI3K and MAPK signaling pathways using microRNAs to inhibit tumor growth and metastasis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1912.