Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo

• Published in: Oncogene Vol. 33; no. 29; pp. 3784 - 3793
• Main Authors: Zhou, Z N, Sharma, V P, Beaty, B T, Roh-Johnson, M, Peterson, E A, Van Rooijen, N, Kenny, P A, Wiley, H S, Condeelis, J S, Segall, J E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.07.2014; Nature Publishing Group
• Subjects: 631/250/2504/342; 631/80/86; 692/699/67/1347; 692/699/67/322; Animals; Apoptosis; Autocrine Communication - genetics; Autocrine mechanisms; Autocrine signalling; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Line, Tumor; Cell Movement - genetics; Colony-stimulating factor; CORTACTIN; Epidermal growth factor; Epidermal growth factor receptors; Estrogen receptors; Female; Gelatinase A; Gelatinase B; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; GROWTH-FACTOR; HB-EGF; Heparin-binding EGF-like Growth Factor; Human Genetics; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Internal Medicine; INVADOPODIA; Kinases; LIGANDS; LIPOSOME-MEDIATED DEPLETION; Macrophage colony-stimulating factor; Macrophages; Macrophages - immunology; MAMMARY-TUMORS; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medicine; Medicine & Public Health; Metalloproteinase; Metastases; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Oncology; original-article; PARACRINE LOOP; Paracrine signalling; Physiological aspects; RECEPTOR; Receptor, Epidermal Growth Factor - metabolism; SQUAMOUS-CELL CARCINOMA; Tumor Burden; Tumor cells; Tumors; metastasis; EGFR; breast cancer invasion; HBEGF
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.363

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.