PDGFRα and β Play Critical Roles in Mediating Foxq1-Driven Breast Cancer Stemness and Chemoresistance
| Autor: | Fred R. Miller, Cecilia L. Speyer, Guojun Wu, Yongzhong Zhao, Wei Chen, Fanyan Meng, David H. Gorski, Bin Zhang |
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| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Receptor Platelet-Derived Growth Factor alpha Antineoplastic Agents Breast Neoplasms Mammary Neoplasms Animal Biology medicine.disease_cause Article Metastasis Receptor Platelet-Derived Growth Factor beta Mice Twist transcription factor Cell Movement medicine Animals Humans Gene silencing Transcription factor Cell Proliferation Oligonucleotide Array Sequence Analysis Regulation of gene expression Gene knockdown Gene Expression Profiling Twist-Related Protein 1 Nuclear Proteins Cancer Forkhead Transcription Factors medicine.disease Gene Expression Regulation Neoplastic Oncology Drug Resistance Neoplasm Neoplastic Stem Cells Cancer research Female Carcinogenesis Neoplasm Transplantation |
| Zdroj: | Cancer Research. 75:584-593 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-13-3029 |
| Popis: | 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, pharmacologic 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, with potential implications for developing novel therapeutic combinations to treat breast cancer. Cancer Res; 75(3); 584–93. ©2014 AACR. |
| Databáze: | OpenAIRE |
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