title: Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo.
abstract: Increased expression of HBEGF in estrogen receptor-negative breast tumors is correlated with enhanced metastasis to distant organ sites and more rapid disease recurrence upon removal of the primary tumor. Our previous work has demonstrated a paracrine loop between breast cancer cells and macrophages in which the tumor cells are capable of stimulating macrophages through the secretion of colony-stimulating factor-1 while the tumor-associated macrophages (TAMs), in turn, aid in tumor cell invasion by secreting epidermal growth factor. To determine how the autocrine expression of epidermal growth factor receptor (EGFR) ligands by carcinoma cells would affect this paracrine loop mechanism, and in particular whether tumor cell invasion depends on spatial ligand gradients generated by TAMs, we generated cell lines with increased HBEGF expression. We found that autocrine HBEGF expression enhanced in vivo intravasation and metastasis and resulted in a novel phenomenon in which macrophages were no longer required for in vivo invasion of breast cancer cells. In vitro studies revealed that expression of HBEGF enhanced invadopodium formation, thus providing a mechanism for cell autonomous invasion. The increased invadopodium formation was directly dependent on EGFR signaling, as demonstrated by a rapid decrease in invadopodia upon inhibition of autocrine HBEGF/EGFR signaling as well as inhibition of signaling downstream of EGFR activation. HBEGF expression also resulted in enhanced invadopodium function via upregulation of matrix metalloprotease 2 (MMP2) and MMP9 expression levels. We conclude that high levels of HBEGF expression can short-circuit the tumor cell/macrophage paracrine invasion loop, resulting in enhanced tumor invasion that is independent of macrophage signaling.
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Z N
authors.initials: ZN
authors.lastname: Zhou
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: V P
authors.initials: VP
authors.lastname: Sharma
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Beaty
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Roh-Johnson
authors.affiliation: Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Peterson
authors.affiliation: Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Van Rooijen
authors.affiliation: Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Kenny
authors.affiliation: 1] Systems Biology Program, Pacific Northwest National Laboratory, Richland, WA, USA [2] Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Wiley
authors.affiliation: 1] Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA [2] Gruss Lipper Center for Biophotonics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Condeelis
authors.affiliation: 1] Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA [2] Gruss Lipper Center for Biophotonics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Segall
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D047368:Tumor Burden
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D066246:ErbB Receptors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9