Abstract Triple-negative breast cancer TNBC is associated with aggressive metastasis and poor clinical outcomes due to a lack of effective treatment options. Therefore, new drugs that effectively target both cancer cell proliferation and metastasis are needed to improve clinical outcomes. The 90-kDa molecular chaperone heat-shock protein, HSP90 has been implicated in cancer progression and metastasis by modulating the stabilization and maturation of many oncogenic proteins. Our objective was to investigate the mechanism of action of C-terminal HSP90 inhibitor, deguelin-derivative L80 on TNBC proliferation and metastasis in vitro and in vivo. L80 induced apoptosis and suppression of cell viability in TNBC cell lines via inhibition of Akt activation with concomitant nuclear accumulation of p27. L80 treatment also caused a marked suppression of cell migration and invasion. These responses were associated with inhibition of STAT3 phosphorylation (Tyr705) as evidenced by downregulation of STAT3 downstream target genes including cyclin D1 and survivin. The syngeneic orthotopic mouse model with 4T1 cells, L80 administration resulted in significant reduction in tumor growth together with decreased number of Ki-67-positive cells and downregulation of phospho-STAT3. Double-label immunofluorescence analysis showed that individuals receiving L80 exhibited a marked reduction in co-localization and expression of HIF-1α and HSP90 compared to their control groups in vivo. Finally, we observed that L80 administration significantly suppressed lung metastasis, as determined by in vivo bioluminescent imaging system. Our findings suggest that L80 may be potentially effective for the treatment for metastatic TNBC patients. Note: This abstract was not presented at the meeting. Citation Format: Tae-Min Cho, Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Ji Young Kim, Jeewoo Lee, Jae Hong Seo. Deguelin-derivative, L80 suppresses tumor growth and metastasis via inhibition of STAT3 activation in triple-negative breast cancer [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 2121. doi:10.1158/1538-7445.AM2017-2121