Abstract
Cancer stem cells (CSCs), a rare population of tumor cells with high self-renewability potential, have gained increasing attention due to their contribution to chemoresistance and metastasis. We have previously demonstrated a critical role for the actin-bundling protein (fascin) in mediating breast cancer chemoresistance through activation of focal adhesion kinase (FAK). The latter is known to trigger the β-catenin signaling pathway. Whether fascin activation of FAK would ultimately trigger β-catenin signaling pathway has not been elucidated. Here, we assessed the effect of fascin manipulation in breast cancer cells on triggering β-catenin downstream targets and its dependence on FAK. Gain and loss of fascin expression showed its direct effect on the constitutive expression of β-catenin downstream targets and enhancement of self-renewability. In addition, fascin was essential for glycogen synthase kinase 3β inhibitor–mediated inducible expression and function of the β-catenin downstream targets. Importantly, fascin-mediated constitutive and inducible expression of β-catenin downstream targets, as well as its subsequent effect on CSC function, was at least partially FAK dependent. To assess the clinical relevance of the in vitro findings, we evaluated the consequence of fascin, FAK, and β-catenin downstream target coexpression on the outcome of breast cancer patient survival. Patients with coexpression of fascinhigh and FAKhigh or high β-catenin downstream targets showed the worst survival outcome, whereas in fascinlow, patient coexpression of FAKhigh or high β-catenin targets had less significant effect on the survival. Altogether, our data demonstrated the critical role of fascin-mediated β-catenin activation and its dependence on intact FAK signaling to promote breast CSC function. These findings suggest that targeting of fascin–FAK-β-catenin axis may provide a novel therapeutic approach for eradication of breast cancer from the root.
Highlights
Recent years have witnessed increased overall survival of breast cancer patients that could be attributed to early detection and the substantial progress in developing more effective therapies
We demonstrated that fascin expression in breast cancer cells induces β1 integrin to sustain focal adhesion kinase (FAK) activation [7], which is required for nuclear translocation of β-catenin and transcriptional activation of the β-catenin target genes [9]
Fascin-mediated induction of β-catenin downstream targets after fascin rescued (FORF) in fascin− MDA-MB-231 cells was diminished when treated with focal adhesion kinase inhibitor (FAKi)
Summary
Recent years have witnessed increased overall survival of breast cancer patients that could be attributed to early detection and the substantial progress in developing more effective therapies. Fascin is an actin-bundling protein that is induced in many neoplasms including breast cancer [3], and we have previously showed that it enhances metastasis [4] and confers resistance to chemotherapy [5] through direct regulation of CSC population [6]. We have demonstrated that fascin enhances β1 integrin expression, a critical step for activation of the focal adhesion kinase (FAK) and subsequent regulation of CSC function [7]. Other studies showed that FAK expression, which is often enhanced in breast cancer [8], is required for nuclear translocation of β-catenin and transcriptional activation of the β-catenin target genes [9]. Whether fascin activation of FAK regulates breast CSCs through β-catenin signaling has not been elucidated
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