title: Hepatocyte growth factor-like protein is a positive regulator of early mammary gland ductal morphogenesis.
abstract: The Ron receptor tyrosine kinase regulates multiple cellular processes and is important during mammary gland development and tumor progression. Hepatocyte growth factor-like protein [HGFL] is the only known ligand for the Ron receptor and recent studies have identified major roles for HGFL during breast cancer metastasis. Understanding the functional importance HGFL during mammary gland development will provide significant insights onto its contribution during tumor development and metastasis. In this study, we assessed the role of HGFL during postnatal mammary gland development using mice that were either proficient [HGFL +/+] or deficient [HGFL-/-] for HGFL. Postnatal ductal morphology and stromal cell associations were analyzed at multiple time points through puberty until adulthood. HGFL deficiency resulted in several mammary gland developmental defects including smaller terminal end buds [TEBs], significantly fewer TEBs, and delayed ductal outgrowth during early puberty. Additionally, HGFL deficient animals exhibited significantly altered TEB epithelial cell turnover with decreased proliferation and increased apoptosis coupled with decreased TEB diameter. Macrophage recruitment to the TEBs was also significantly decreased in the HGFL-/- mice compared to controls. Moreover, the levels of STAT3 mRNA as well as the phosphorylation status of this protein were lower in the HGFL-/- mammary glands compared to controls. Taken together, our data provide the first evidence for HGFL as a positive regulator of mammary gland ductal morphogenesis by controlling overall epithelial cell turnover, macrophage recruitment, and STAT3 activation in the developing mammary gland. With a function in early mammary gland development, HGFL represents a potential target for the development of novel breast cancer therapies.
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors: Devikala
authors: D
authors: Gurusamy
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors: Sasha J
authors: SJ
authors: Ruiz-Torres
authors: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors: Abby L
authors: AL
authors: Johnson
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors: Dana A
authors: DA
authors: Smith
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA; Research Service, Cincinnati Veterans Hospital Medical Center, Cincinnati, OH 45267-0521, USA. Electronic address: susan.waltz@uc.edu.
authors: Susan E
authors: SE
authors: Waltz
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: Cell turnover; HGFL; Macrophages; Mammary gland development; Ron receptor; STAT3