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.
Highlights
Breast cancer is the most commonly diagnosed cancer amongst women in the US, with approximately 12% of women expected to develop invasive breast cancer during their lifetime [1]
Similar to the hyperplasia data, a significant decrease in local tumor cell invasion was apparent in the mammary glands of MMTV-RonHGFL−/− mice at 4 and 6 months compared to MMTV-RonHGFL+/+ mice (Figure 1C)
The study presented here is the first to examine the role of endogenous hepatocyte growth factor-like protein (HGFL) in the context of Ron overexpression, a condition associated with poor prognosis in human tumors [7]
Summary
Breast cancer is the most commonly diagnosed cancer amongst women in the US, with approximately 12% of women expected to develop invasive breast cancer during their lifetime [1]. While treatment advances and earlier detection have contributed to a decline in death rates for breast cancer patients, 20 to 30% of patients initially diagnosed with early stage disease will develop metastatic breast cancer, many in spite of successful treatment of a primary tumor, accounting for approximately 40,000 deaths annually [1]. Ron expression is minimally detectable in normal epithelial cells of the mammary gland but is overexpressed in a majority of human breast cancers [2,3,4]. To determine if Ron overexpression could be causative in disease progression, mice that overexpress Ron selectively in the mammary epithelium (MMTV-Ron mice) were generated [4] In these animals, Ron overexpression was sufficient to induce aggressive breast tumors that were highly metastatic. Mounting evidence indicates that Ron overexpression is a causative factor contributing to aggressive breast cancer and metastatic disease
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