Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions.

Our previous investigations using cell models of tamoxifen resistance have shown that the acquisition of an endocrine-insensitive state is accompanied by an invasive in vitro phenotype. In this study, we wished to determine whether this was specifically related to partial oestrogen receptor agonists or whether similar phenomena arise with the newer 'pure' anti-oestrogens, exemplified by fulvestrant. Our data demonstrate that the development of fulvestrant resistance in two breast cancer cell lines, MCF7 and T47D, is accompanied by an augmented migratory and invasive phenotype in vitro and overexpression of the HGF/SF receptor, c-Met. Importantly, upregulated c-Met expression in these cells facilitates their stimulation by HGF/SF-secreting stromal fibroblasts, leading to the activation of Src, Akt and ERK1/2 and a profound enhancement of their aggressive phenotype in vitro. These effects could be specifically attributable to activation of the c-Met receptor since the inclusion of neutralising antibodies to c-Met, or siRNA-mediated knockdown of c-Met expression, suppressed both invasion and migration stimulated by either exogenous HGF/SF, fibroblast-conditioned medium or following co-culture with fibroblast cells. Together, these in vitro data suggest that the development of fulvestrant resistance in vivo may confer a metastatic advantage to the cells by allowing their migratory and invasive behaviour to be augmented by surrounding stromal cells.