Decreased autocrine EGFR signaling in metastatic breast cancer cells inhibits tumor growth in bone and mammary fat pad

• Published in: PloS one 2012-01, Vol.7 (1), p.e30255-e30255
• Main Authors: Nickerson, Nicole K, Mohammad, Khalid S, Gilmore, Jennifer L, Crismore, Erin, Bruzzaniti, Angela, Guise, Theresa A, Foley, John
• Format: Article
• Language: English
• Subjects: Amphiregulin; Animals; Antibodies; Autocrine signalling; Biocompatibility; Biology; Biomedical materials; Bone and Bones - pathology; Bone cancer; Bone growth; Bone marrow; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer cells; Cancer metastasis; Cancer treatment; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Colony-stimulating factor; EGF Family of Proteins; Endocrinology; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; ErbB protein; Female; Gelatinase B; Gene expression; Glycoproteins - metabolism; Growth; Growth factors; Humans; Inoculation; Intercellular Signaling Peptides and Proteins - metabolism; Leukocyte migration; Ligands; Lung cancer; Macrophages; Mammary gland; Mammary Glands, Animal - pathology; Matrix metalloproteinase; Medicine; Metalloproteinase; Metastases; Metastasis; Mice; Mice, Nude; Morphogenesis; Osteoblasts; Osteoclasts; Osteogenesis - genetics; Osteogenesis - physiology; Phosphorylation - genetics; Phosphorylation - physiology; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; RNA, Small Interfering; Rodents; Signal Transduction - genetics; Signal Transduction - physiology; Stem cells; Survival; Tumors; Vascular endothelial growth factor; X-Ray Microtomography
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030255

Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR) and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231), and agonist-induced signaling was examined in both breast cancer and osteoblast-like cells. Both paracrine and autocrine EGFR signaling were inhibited with a neutralizing amphiregulin antibody, PAR34, whereas shRNA to the EGFR was used to specifically block autocrine signaling in MDA-231 cells. The impact of these was evaluated with proliferation, migration and gene expression assays. Breast cancer metastasis to bone was modeled in female athymic nude mice with intratibial inoculation of MDA-231 cells, and cancer cell-bone marrow co-cultures. EGFR knockdown, but not PAR34 treatment, decreased osteoclasts formed in vitro (p