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Abstract
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<0.01), reduced osteolytic lesion tumor volume (p<0.01), increased survivorship in vivo (p<0.001), and resulted in decreased MDA-231 growth in the fat pad (p<0.01). Fat pad shEGFR-MDA-231 tumors produced in nude mice had increased necrotic areas and decreased CD31-positive vasculature. shEGFR-MDA-231 cells also produced decreased levels of the proangiogenic molecules macrophage colony stimulating factor-1 (MCSF-1) and matrix metalloproteinase 9 (MMP9), both of which were decreased by EGFR inhibitors in a panel of EGFR-positive breast cancer cells. Thus, inhibiting autocrine EGFR signaling in breast cancer cells may provide a means for reducing paracrine factor production that facilitates microenvironment support in the bone and mammary gland.
Highlights
The epidermal growth factor (EGFR) has long been recognized as a therapeutic target in breast and other epithelial cancers due to its ability to potently stimulate cell proliferation, motility, and invasion
Amphiregulin is highly secreted by MDA-231 cells Previously we determined a subline of the aggressive breast cancer cell line MDA-231 efficiently colonizes mouse bone after intracardiac inoculation, expresses high levels of EGFR protein and modest levels of the ErbB2 and ErbB3 receptors, and sheds AREG [20]
To more completely evaluate EGFR ligand production in these cells, we examined the expression of five EGFR ligands, including epidermal growth factor (EGF), AREG, betacellulin, heparin-binding EGF (HB-EGF), and transforming growth factor a (TGFa) using ELISA for both conditioned media and membrane extracts
Summary
The epidermal growth factor (EGFR) has long been recognized as a therapeutic target in breast and other epithelial cancers due to its ability to potently stimulate cell proliferation, motility, and invasion. The EGFR is activated by a family of ligands that include epidermal growth factor (EGF), Amphiregulin (AREG), transforming growth factor a (TGFa), heparin-binding EGF (HBEGF), betacellulin, epiregulin, epigen, and Neuregulin 2b [1] These factors are synthesized as plasma membrane proteins tethered by a transmembrane domain, requiring proteolytic cleavage to be accessible to receptors [2]. Co-expression of the ADAM17 protease and the TGFa ligand in primary basal tumors has been associated with reduced survival [12] These observations suggest that more aggressive basal-like breast cancers have the capacity to be stimulated by autocrine EGFR signaling, whereas the ligands produced by other subtypes of breast cancer (luminal, HER2 positive) may serve as paracrine signaling molecules [13]
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