Abstract 38: The role of autocrine epidermal growth factor receptor (EGFR) signaling in breast cancer metastasis

Abstract

Abstract The majority of breast cancer deaths are due to the development of metastatic disease. The metastatic cascade consists of a series of steps and includes primary tumor growth and angiogenesis, invasion, intravasation, cell survival in circulation, extravasation and sustained growth at secondary organ sites to form micrometastases. Previous studies have shown that overexpression of the epidermal growth factor receptor (EGFR; ErbB1; Her1) increases tumor cell motility, intravasation and motility. In addition, it has been demonstrated that the metastatic potential of cancer cells depends not only on their intrinsic characteristics but also on their cooperative interaction with the tumor microenvironment. For instance, imposed gradients of EGF or colony-stimulating factor-1 (CSF-1) can stimulate invasion via an EGF/CSF-1 paracrine loop between tumor cells and macrophages. Because breast malignancies exhibiting increased expression of the epidermal growth factor (EGF) family of receptors and their cognate ligands are associated with more biologically aggressive disease and poorer patient prognosis, we decided to study how expression of certain members of the EGF family of ligands in the context of ErbB1 overexpression can affect the processes of invasion, intravasation and metastasis using in vitro and in vivo systems. Based on initial Oncomine cancer gene expression analysis, heparin-binding epidermal growth factor-like growth factor (HB-EGF) overexpression was correlated with more rapid recurrence of disease in breast cancer and thus, we decided to focus our study this ligand. Briefly, MTLn3 rat mammary adenocarcinoma cells and human MDA-MB 231 breast adenocarcimona cells were transduced to overexpress HB-EGF. HB-EGF expression did not significantly affect in vitro or in vivo growth rate. In vitro microchemotaxis and invasion assays to study chemotaxis and invasion, respectively, in the presence and absence of EGF, demonstrated that random motility and spontaneous invasion were both enhanced in the presence of HB-EGF expression. Interestingly, EGF-induced chemotaxis and EGF-induced in vivo invasion were both suppressed. In vivo studies show that tumor cells expressing HB-EGF not only display increased metastasis to the lungs and extravasation from circulation, but also significantly enhanced macrophage recruitment and exerted an angiogenic effect. These findings suggest that a better understanding of the role of HB-EGF in breast cancer will aid in directing and modifying therapeutic approaches aimed at inactivating the ErbB ligand/EGFR system as well as developing approaches based on the EGF family of ligands as a target for the clinical treatment of breast cancer, ultimately leading to improved patient survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 38. doi:1538-7445.AM2012-38