HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses.
The Ron receptor is overexpressed in human breast cancers and is associated with heightened metastasis and poor survival. Ron overexpression in the mammary epithelium of mice is sufficient to induce aggressive mammary tumors with a high degree of metastasis. Despite the well-documented role of Ron in breast cancer, few studies have examined the necessity of the endogenous Ron ligand, hepatocyte growth factor-like protein (HGFL) in mammary tumorigenesis. Herein, mammary tumor growth and metastasis were examined in mice overexpressing Ron in the mammary epithelium with or without HGFL. HGFL ablation decreased oncogenic Ron activation and delayed mammary tumor initiation. HGFL was important for tumor cell proliferation and survival. HGFL loss resulted in increased numbers of macrophages and T-cells within the tumor. T-cell proliferation and cytotoxicity dramatically increased in HGFL deficient mice. Biochemical analysis of HGFL proficient tumors showed increased local HGFL production, with HGFL loss decreasing β-catenin expression and NF-κB activation. Re-expression of HGFL in HGFL deficient tumor cells stimulated cell migration and invasion with coordinate activation of NF-κB and reduced apoptosis. Together, these results demonstrate critical in vivo functions for HGFL in promoting breast tumorigenesis and suggest that targeting HGFL may inhibit tumor growth and reactivate anti-tumor immune responses.
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Nancy M
NM
Benight
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Purnima K
PK
Wagh
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.|Susan G. Komen, Scientific Grants Manager, Dallas, TX 75244, USA.
Glendon M
GM
Zinser
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.|Senior Medical Writer, Optum, Eden Prairie, MN 55344, USA.
Belinda E
BE
Peace
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
William D
WD
Stuart
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Juozas
J
Vasiliauskas
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Peterson
P
Pathrose
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Sandra L
SL
Starnes
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.|Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45267, USA.
Susan E
SE
Waltz
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000276:immunology / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism
D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
Ron receptor; breast cancer; hepatocyte growth factor-like protein; receptor tyrosine kinase