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Cancer stem cells
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 in-hibited AKT/MEK/ERK/JAK2/STAT3 signaling in TNBC Ampicillin 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.
Triple-negative breast cancer (TNBC) accounts for 10–15% of all diagnosed breast cancers and has an aggressive clinical course due to a lack of therapeutic cellular targets . Accumulating clinical evidence demonstrates that TNBC is biologically more aggressive and has a higher Ki-67 proliferation index with greater metastatic potential than other breast cancer subtypes [2,3]. Consensus toward a standard ther-apeutic strategy is lacking, and the overall five-year survival rate is less than 30% in TNBC patients who present with a distant recurrence .
Heat-shock protein 90 (HSP90) is a ubiquitous molecular chaperone that is evolutionally conserved and highly abundant, comprising 1–2% of total cellular protein under normal physiological conditions .
During cancer progression, this proportion increases by 2–10-fold in tumor cells . HSP90 plays important roles in numerous biological functions and diverse processes including cell survival, proliferation, cancer progression and metastasis by regulating stability, maturation and the conformational changes of various proteins [7–9]. Elevated HSP90 levels are frequently observed in TNBC patients, which is asso-ciated with a higher risk of recurrence, distant metastasis and a poor prognosis . HSP90 dysfunction with natural and synthetic in-hibitors attenuates cell proliferation, survival and cell dissemination in many cancer types via dysregulation of HSP90 client oncoproteins in-cluding HER2, EGFR, VEGF, JAK, STAT, and AKT [11–14].
Of particular note, HSP90 is essential for the functional competence of STAT3 activity that governs the tumor microenvironment and cancer
1 T-M. Cho and JY. Kim contributed equally to this work.
Fig. 1. L80 suppresses TNBC cell viability in a dose- and time-dependent manner. (A) Chemical structures of deguelin and L80. (B) Changes in cellular morphology in MDA-MB-231, 4T1, BT549 and Hs578T cells after L80 (5 μM) treatment for 72 h as seen through phase contrast microscopy. (C) Effect of L80 on cell viability. Cells were treated with various concentrations of L80 (0.2–20 μM) for 48 h and 72 h. Cell viability was determined by MTS assay (*p < 0.05, versus DMSO control). The results are presented as mean ± SEM of at least three independent experiments and analyzed by two-way ANOVA followed by Bonferroni's post hoc test.