Abstract 4092: PDGFRα and β play critical roles in mediating Foxq1-driven breast cancer stemness and chemoresistance

Abstract

Many epithelial-mesenchymal transition (EMT)-promoting transcription factors have been implicated in tumorigenesis and metastasis, as well as chemoresistance of cancer. However, the underlying mechanisms mediating these processes are unclear. Here we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. Using an expression profiling assay, we identified Twist1, Zeb2, and PDGFRα and β as Foxq1 downstream targets. We further show that PDGFRα and β can be directly regulated by Foxq1 or indirectly regulated through the Foxq1/Twist1 axis. Knockdown of both PDGFRα and β results in more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown of either PDGFRα or β alone. In addition, PDGFRβ is a more potent mediator of Foxq1-promoted stemness traits than PDGFRα. Finally, pharmacological inhibition or gene silencing of PDGFRs sensitizes mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively implicate PDGFRs as critical mediators of breast cancer oncogenesis and chemoresistance driven by Foxq1, and may have important implications for the development of novel combinational therapeutics against breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Fanyan Meng, Cecilia Speyer, Bin Zhang, Yongzhong Zhao, Wei Chen, David Gorski, Fred R. Miller, Guojun Wu. PDGFRα and β play critical roles in mediating Foxq1-driven breast cancer stemness and chemoresistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4092. doi:10.1158/1538-7445.AM2015-4092

Novel mechanistic targets of Forkhead box Q1 transcription factor in human breast cancer cells

“…Transcriptional inactivation of E-cadherin by FoxQ1 overexpression was also demonstrated in this study (8). Subsequently, platelet-derived growth factor receptor α/β were identified as additional downstream targets of FoxQ1 in promotion of breast cancer stem cell-like phenotype as well as chemoresistance (9). We have also shown previously that FoxQ1 promotes breast cancer stem-like phenotype in a luminal-type (MCF-7) and a basal-like (SUM159) cell line by causing direct transcriptional repression of the tumor suppressor Dachshund homolog 1 (DACH1) (10).…”

“…Published studies have revealed multiple downstream targets of FoxQ1 in breast cancer (7)(8)(9)(10)(11)(12). For example, Zhang et al (7) showed downregulation of CDH1 (Ecadherin ) but upregulation of mesenchymal markers including CTNNA1 (catenin alpha 1), CDH2 (N-cadherin), and FN1 (fibronectin 1) in highly metastatic breast cancer cell lines (e.g., MDA-MB-435, MDA-MB-231, SUM149, etc.)…”

“…The transcription factor forkhead box Q1 (FoxQ1) has recently emerged as a key player in the pathogenesis of breast cancer (7)(8)(9). Zhang et al (7) were the first to demonstrate a role for FoxQ1 in epithelialmesenchymal transition (EMT) in breast cancer metastasis using a cross-species gene expression profiling strategy.…”

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

“…Specifically, FOXQ1 is overexpressed in colorectal cancer and it promotes tumor growth and/or metastatic activity by increasing PI3K/AKT signaling . EMT, which is related to tumor stemness and chemoresistance, is promoted by FOXQ1 in nonsmall cell lung cancer and breast cancer . Notably, the expression of EMT markers and upregulation of PI3K signals in Ewing sarcoma are associated with worse prognosis .…”

“…32,33 EMT, which is related to tumor stemness and chemoresistance, is promoted by FOXQ1 in nonsmall cell lung cancer and breast cancer. 34,35 Notably, the expression of EMT markers and upregulation of PI3K signals in Ewing sarcoma are associated with worse prognosis. 36 Our current study indicates that FOXQ1 interacts with EWS-FLI1 and increases its enhancer activity toward target genes.…”