HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses

// Nancy M. Benight 1 , Purnima K. Wagh 1 , Glendon M. Zinser 1, 4 , Belinda E. Peace 1, 5 , William D. Stuart 1 , Juozas Vasiliauskas 1 , Peterson Pathrose 2 , Sandra L. Starnes 2 , Susan E. Waltz 1, 3 1 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA 2 Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA 3 Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45267, USA 4 Susan G. Komen, Scientific Grants Manager, Dallas, TX 75244, USA 5 Senior Medical Writer, Optum, Eden Prairie, MN 55344, USA Correspondence to: Susan E. Waltz, e-mail: susan.waltz@uc.edu Keywords: receptor tyrosine kinase, Ron receptor, hepatocyte growth factor-like protein, breast cancer Received: January 15, 2015      Accepted: April 07, 2015      Published: April 17, 2015 ABSTRACT 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.