Abstract 4192: C-terminal HSP90 inhibitor, L80, targets cancer stem cell (CSC)-like property and suppresses metastasis via JAK/STAT3 inactivation in triple-negative breast cancer

Abstract

Abstract Purpose: Triple-negative breast cancer (TNBC) harbors high level of cancer stem cell (CSC)-like populations, which is associated with aggressive phenotype leading to tumor cell dissemination and poor clinical outcomes. Therefore, new drugs that effectively target both CSCs and tumor bulk cells 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 effects of L80 on cancer stem-like characteristics, cell proliferation and metastasis in TNBC in vitro and in vivo. Experimental Design: The effect of L80 on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis and mammosphere-forming ability and expression of JAK/STAT3 signaling-related factors. An orthotopic injection model with 4T1 mammospheres with self-renewability was used to examine the effect of L80 on tumor growth, angiogenesis and metastasis. Results: L80 treatment caused a significant induction of apoptosis, accompanied by caspase-3/-7 activation and the dysregulation of JAK/STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like trait, concomitant with a significant suppression of mammosphere formation. To confirm the physiological relevance of our in vitro findings, we examined the impact of L80 on allografted tumor growth, angiogenesis and metastasis in vivo. L80 administration impedes tumor growth and subsequently suppresses angiogenesis, as evidenced by a marked reduction in number of CD31-positive microvessels in the L80-treated groups compared to their counterparts. L80 administration leads to a significant reduction in lung and liver metastases, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. These responses were intimately associated with dysregulation of JAK/STAT3 activation. Conclusion: C-terminal HSP90 inhibitor, L80 suppresses tumor growth and metastasis via suppression of JAK/STAT3 activity and CSC-like property. These findings suggest that HSP90 could be a promising target for treatment of metastatic TNBC. Citation Format: Tae-Min Cho, Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Seojin Jang, Jeewoo Lee, Ji Young Kim, Jae Hong Seo. C-terminal HSP90 inhibitor, L80, targets cancer stem cell (CSC)-like property and suppresses metastasis via JAK/STAT3 inactivation in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4192.