Abstract 3704: MicroRNA-3977 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting FoxM1

Abstract

Triple negative breast cancer (TNBC) is an aggressive type of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). TNBC is associated with poor prognosis, high rates of relapse and distant metastasis despite surgery and adjuvant chemotherapy. The lack of effective targeted therapies for TNBC requires new therapeutic approaches. The Forkhead box protein M1 (FoxM1) is a member of forkhead superfamily transcription factors that has been associated with normal cell growth and proliferation through cell cycle transition and mitotic spindle control. FoxM1 is also identified as a master regulator of tumor metastasis. Based on analysis of pooled clinical datasets derived from online accessible databases as Breast Cancer Gene-Expression Miner v4.3 and Kaplan-Meier plotter, the expression and prognostic values of FoxM1 increase in TNBC compare with other breast cancer subtypes. Directly binding to the 3'-untranslated region (3' UTR) of FoxM1 mRNAs suppress its high expression in TNBC that leads to inhibition of cell proliferation, motility, and invasion. These results implied that FoxM1 is an essential poor prognostic factor and promising candidate target in the treatment of TNBC. We identified miR-3977 as a potential regulator of FoxM1 by using in silico prediction algorithms, and we investigated its role in TNBC. In this study, we found miR-3977 expression is significantly suppressed in TNBC cell lines and inversely correlated with FoxM1 levels. We demonstrate that miR-3977 directly bound to the 3′ UTR of FoxM1 mRNA and repressed its expression. We also find reduced miR-3977 expression is associated with shorter patient survival in TNBC based on Kaplan-Meier plotter database. Moreover, in vivo delivery of miR-3977 nanoparticles inhibited FoxM1 expression and tumor growth in TNBC xenograft mouse models. In conclusion, we provide the first evidence that miR-3977 functions as a tumor suppressor and gain of miR-3977 expression leads to decrease in FoxM1 expression and inhibits to cell growth, colony formation, invasion, and progression of TNBC. Taken together, our data suggest that miR-3977-based gene therapy is a potential therapeutic strategy in TNBC. Citation Format: Selda Karamil, Nuray Altintas, Bulent Ozpolat. MicroRNA-3977 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting FoxM1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3704.