title: 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, 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.
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Fanyan
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Speyer
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn Mount Sinai School of Medicine, New York, New York.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn Mount Sinai School of Medicine, New York, New York.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Biostatistic Core facility, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: David H
authors.initials: DH
authors.lastname: Gorski
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Miller
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan. wugu@karmanos.org.
authors.forename: Guojun
authors.initials: G
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C484579:FOXQ1 protein, human; D051858:Forkhead Transcription Factors; C107579:Foxq1 protein, mouse; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta