This study is investigating the role of RET in the functional regulation of ERa and in the response and resistance to endocrine therapies

More than 50% of breast cancers are oestrogen receptor-a (ERa) positive and depend on oestrogen for their growth. Therapies that target the action of oestrogen or ERa are highly effective and in routine clinical use. However, not all tumours respond well and, in many cases, the effectiveness of these agents is limited by the development of resistance. A major mechanism of resistance is via deregulation of receptor tyrosine kinase signaling pathways that result in the activation of ERa in the absence of oestrogen.

We have recently demonstrated that the receptor tyrosine kinase RET is upregulated in a subset of ER-positive breast cancers, and that the RET ligand, GDNF, is an important component of the tumour-mediated inflammatory response (Esseghir et al., 2007; Plaza-Menacho et al., 2007). Our current studies are focussed on elucidating the role of RET in the functional regulation of ERa and in the response and resistance to endocrine therapies in ERa-positive breast cancers. For this we are using a multidisciplinary approach based on in vitro tumour cell studies as well as in the creation of a novel Drosophila model to study the functional interplay of RET and ERa in vivo. The latter has important implications for rapid, high scale throughput and cost effective genetic analysis of key components of signaling pathways in breast cancer and for the screening and assessment of novel therapeutic agents.

This study will lead to a better understanding of why some tumours respond well to endocrine therapy and why others do not. This in turn, will help us identify new therapeutic targets to which drugs can be developed for the treatment of non-responsive tumours or to be used in combination with current treatments to affect an improved killing of the tumour cells.