title: Autocrine CSF1R signaling mediates switching between invasion and proliferation downstream of TGFβ in claudin-low breast tumor cells.
abstract: Patient data suggest that colony-stimulating factor-1 (CSF1) and its receptor (CSF1R) have critical roles during breast cancer progression. We have previously shown that in human breast tumors expressing both CSF1 and CSF1R, invasion in vivo is dependent both on a paracrine interaction with tumor-associated macrophages and an autocrine regulation of CSF1R in the tumor cells themselves. Although the role of the paracrine interaction between tumor cells and macrophages has been extensively studied, very little is known about the mechanism by which the autocrine CSF1R signaling contributes to tumor progression. We show here that breast cancer patients of the claudin-low subtype have significantly increased expression of CSF1R. Using a panel of breast cancer cell lines, we confirm that CSF1R expression is elevated and regulated by TGFβ specifically in claudin-low cell lines. Abrogation of autocrine CSF1R signaling in MDA-MB-231 xenografts (a claudin-low cell line) leads to increased tumor size by enhanced proliferation, but significantly reduced invasion, dissemination and metastasis. Indeed, we show that proliferation and invasion are oppositely regulated by CSF1R downstream of TGFβ only in claudin-low cell lines. Intravital multiphoton imaging revealed that inhibition of CSF1R in the tumor cells leads to decreased in vivo motility and a more cohesive morphology. We show that, both in vitro and in vivo, CSF1R inhibition results in a reversal of claudin-low marker expression by significant upregulation of luminal keratins and tight-junction proteins such as claudins. Finally, we show that artificial overexpression of claudins in MDA-MB-231 cells is sufficient to tip the cells from an invasive state to a proliferative state. Our results suggest that autocrine CSF1R signaling is essential in maintaining low claudin expression and that it mediates a switch between the proliferative and the invasive state in claudin-low tumor cells downstream of TGFβ.
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Patsialou
authors.affiliation: 1] Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA [2] Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pignatelli
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1] Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA [2] Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Entenberg
authors.affiliation: Department of Pathology, Montefiore Medical Center, Bronx, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Oktay
authors.affiliation: 1] Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA [2] Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Condeelis
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D057167:Claudins / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D061986:MCF-7 Cells; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D057167:Claudins; D016212:Transforming Growth Factor beta; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
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