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

Tae Min Cho, Ji Young Kim, Yoon Jae Kim, Daeil Sung, Eunhye Oh, Seojin Jang, Lee Farrand, Van Hai Hoang, Cong Truong Nguyen, Jihyae Ann, Jeewoo Lee, Jae Hong Seo

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)141-153
Number of pages13
JournalCancer Letters
Volume447
DOIs
Publication statusPublished - 2019 Apr 10

Keywords

  • C-terminal HSP90 inhibitor
  • Cancer stem cells
  • L80
  • Metastasis
  • STAT3
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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