C-terminal HSP90 inhibitor L80 elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition

Abstract

Triple-negative breast cancer (TNBC) is an aggressive heterogeneous disease with a divergent profile. It has an earlier tendency to form metastases and is associated with poor clinical outcomes due to the limited treatment options available. Heat-shock protein (HSP90) represents a potential treatment target as it promotes tumor progression and metastasis by modulating the maturation and stabilization of signal transduction proteins. We sought to investigate the efficacy of the C-terminal HSP90 inhibitor L80 on cell proliferation, breast cancer stem cell (BCSC)-like properties, tumor growth and metastasis. L80 suppressed cell viability and concomitantly inhibited AKT/MEK/ERK/JAK2/STAT3 signaling in TNBC cells but did not induce cytotoxicity in normal cells. L80 effectively targeted BCSC-like traits, together with significant reductions in the CD44high/CD24low-population, ALDH1 activity and mammosphere forming-ability. In support of the in vitro observations, L80 administration caused significant impairment in tumor growth, angiogenesis and distant metastases in an orthotopic allograft model with BCSC-enriched cells in vivo. These phenomena were associated with the suppression of BCSC-like characteristics and STAT3 dysfunction. Our findings highlight properties of the L80 compound that may be useful in suppressing metastatic TNBC.