Triple negative breast cancer (TNBC), is a highly heterogeneous and aggressive subtype of breast cancer (BC), which poses a significant clinical challenge. TNBC constitutes about 15-20 % of BC cases, and is characterized by lack of estrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2) receptors. Thus, patients cannot benefit from targeted therapies such as anti-estrogens (eg.Tamoxifen) and anti-HER2 (eg.trastuzumab) treatments. Therefore, identification of new molecular targets and treatment strategies are highly warranted to improve patient outcome. We previously reported that elongation factor 2 kinase (EF-2K) is highly expressed in TNBC cell lines and is associated with poor patient survival and prognosis. Furthermore, in vivo targeting of EF-2K by siRNA nano-therapeutics inhibited cell proliferation, migration/invasion, and significantly decreased tumor growth in 2 different orthotopic TNBC mouse models (MDA MB-231 and MDA MB-436). Collectively, our work suggests that EF-2K is an excellent novel therapeutic target in TNBC. In search of a potential safe and effective EF-2K inhibitor, we identified Thymoquinone (TQ), a dietary natural compound, known to have diverse anti-cancerous properties in several in vitro and in vivo models, including TNBC. However, the mechanism by which TQ mediates its effects are not well elucidated. Our current study is the first to demonstrate that TQ inhibits protein and mRNA expression of EF-2K, as well as its clinically significant downstream targets such as Src/FAK, PI3K/AKT, and CyclinD1; resulting in a significant decrease in proliferation, migration/invasion of TNBC cells. To determine the molecular mechanism by which TQ inhibits EF-2K expression, we investigated if TQ induces tumor suppressor microRNAs that we identified to bind to the 3’-UTR of EF-2K. We found that TQ induces miR-603 expression, which we had reported to directly bind and inhibit EF-2K expression; resulting in decreased TNBC growth and progression, both in vitro and in vivo. Furthermore, we showed that inhibition of nuclear factor kappa B (NF-κB) (a well established target for TQ), also induces miR-603 and inhibits EF-2K expression in TNBC cells. In conclusion, our study is the first to show that TQ treatment decreases EF-2K expression through modulating the NF-κB/miR-603 axis; ultimately resulting in decreased cell proliferation, migration/invasion of TNBC. Our data suggests a novel molecular mechanism for TQ that represents a potential therapeutic strategy in inhibiting TNBC tumor growth and progression.

Citation Format: Nashwa N. Kabil, Recep Bayraktar, Nermin Kahraman, Bulent Ozpolat. Thymoquinone inhibits elongation factor 2 kinase signaling axis by inducing tumor suppressor miR-603 in triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3249. doi:10.1158/1538-7445.AM2017-3249

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.