Abstract 1906: FOXC1 regulates cancer stem cells properties via inducing SMO-independent Gli activation and confers anti-Hedgehog drug resistance in basal-like breast cancer

Abstract

Abstract Basal-like breast cancer (BLBC), an aggressive subtype of breast cancer, are usually associated with high histologic grade, high recurrence rate, short recurrence-free survival, younger patient age, poor outcome, and a propensity to metastasize to the brain and lung. So far, developing targeted therapies against BLBC still remains a great challenge. Uncovering the underlying molecular events and identify therapeutic target becomes highly urgent. Forkhead Box C1 (FOXC1), a biomarker for BLBC, is associated with poor prognosis in patients with BLBC. Here, we found that FOXC1 increases cancer stem cells (CSCs) properties in BLBC cells in vitro and in vivo. FOXC1 activates SMO-independent non-canonical Hedgehog (Hh) signaling pathway, which mediates the effects of FOXC1 on CSCs properties in BLBC cells. Further study showed that the N-terminal of FOXC1 bind directly to the Gli2 transcription factor, which has the highest transcriptional activity in Hh signaling pathway. Here we also found that the elevated expression of FOXC1 induces anti-Hh pathway drug resistance. All of these data demonstrate a novel mechanism underlying the regulation of CSC properties and the poor prognosis of BLBC patients, and may provide new insight into anti-CSC therapy resistance. Thus, our study provides a strong rationale for developing FOXC1-targeted therapy for treating BLBC patients. Citation Format: Bingchen Han, Yanli Jin, Shikha Bose, Xiao Zhang, Ying Qu, Beth Y. Karlan, Armando E. Giuliano, Xiaojiang Cui. FOXC1 regulates cancer stem cells properties via inducing SMO-independent Gli activation and confers anti-Hedgehog drug resistance in basal-like breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1906. doi:10.1158/1538-7445.AM2014-1906