ER Negative Endocrine Resistant Breast Cancer

Current strategies for the treatment of ER negative endocrine resistant breast cancer, outside of conventional chemotherapy, are extremely limited. Some success has recently been derived from the increasing use of trastuzumab in women with HER2 over-expressing tumours, although this is a relatively small cohort of patients. Disappointingly, responses to gefitinib are similarly restricted, despite the elevated expression of the EGFR in many ER negative tumours.

At presence two further approaches are being pursued. Firstly, considerable effort is being made to define the growth and survival pathways being used by these cells and our microarray and protein analysis have revealed a potential role for c-Met in ER negative, faslodex resistant breast cancer cells (see Chapter 8). This increase in c-Met confers a greatly increased sensitivity to exogenous HGF, which promotes their further invasiveness when stimulated by the exogenous ligand or by co-culturing cells with fibroblasts that produce large quantities of this growth factor (Hiscox et al., 2006a). Such data place the Met receptor centrally in inva-siveness during adaptation to faslodex and its relevance to other forms of resistance is currently being investigated. Secondly, equal effort is being made to coax ER negative cells to re-express ERs, including the use of signal transduction inhibitors to signalling elements thought to reduce ER expression (e.g. parthenalide, an NFkB inhibitor) and agents designed to reverse ER gene silencing (e.g. 5-AZA, a methy-lase inhibitor). It is hoped that ER re-expression will restore endocrine response in patients not normally considered for endocrine measures and limit other adverse features associated with ER negative disease. Interestingly, the use of 5-AZA in ER positive tamoxifen resistant breast cancer cells in vitro promotes the expression of previously silenced tumour suppressor genes to halt cell growth (see Chapter 4), suggesting a value for this agent in ER positive and ER negative endocrine resistant breast cancer.

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