Sensitisation To Stromalderived Growth Factors Through Cmet Overexpression Occurs In Endocrineresistant Cells

Interestingly, array analysis of ER-negative, faslodex-resistant MCF7 cells has revealed significantly elevated levels of the HGF/SF receptor gene, c-Met. Furthermore, this is reflected at protein level and results in cells which are highly sensitive to exogenous HGF/SF ligand (66). Activation of the receptor tyrosine kinase, c-Met, promotes a diverse array of cellular responses resulting in cell 'scattering' and increased invasion (67,68). These in vitro observations have suggested a role for c-Met signalling as a promoter of tumour progression and metastasis in vivo. In this context, c-Met expressed on epithelial tumour cells may be activated in an autocrine manner or by ligand secreted by cells of the surrounding stroma (69,70). Furthermore, high levels of c-Met in breast tumours correlate with a significantly reduced survival rate (69,71-74) with its expression being a stronger prognostic indicator than HER2 and EGFR (75,76). As well as sensitising these cells to HGF/SF, a role for c-Met in the intrinsic, basal invasive capacity of faslodex-resistant cells has been demonstrated by a modest suppression of invasion following siRNA-mediated knockdown of Met activity (66). These in vitro data suggest that the development of an anti-hormone mediated, ER-negative, endocrine-resistant state in vivo may confer a metastatic advantage to the cells by allowing their migratory and invasive behaviour to be augmented by surrounding stromal cells. As such, the potential application of a number of c-Met signalling inhibitors currently under development (77-79) may provide a new option for the suppression of the adverse disease phenotype associated with endocrine resistance.

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