title: Cross-talk between the oestrogen receptor and the human epidermal growth factor receptor (HER) family: Role in resistance to tamoxifen treatment in breast cancer
Creators: name: Tovey, Sian
Publisher: name: University of Glasgow
Year: 2006
Subjects: subject: Oncology, Pharmacology.

description: Tamoxifen is a potent anticancer agent and has long been the standard for adjuvant endocrine therapy in breast cancer in the United Kingdom. Despite this success, resistance to Tamoxifen is a significant clinical problem; almost all patients with metastatic disease experience progression and up to 20% of early breast cancer patients relapse whilst on adjuvant treatment. The primary mechanism of action of Tamoxifen is via competitive inhibition of oestrogen binding to oestrogen receptors. The subsequent reduction in expression of oestrogen related genes such as growth factors and angiogenic factors results in reduced cell proliferation, enhanced apoptosis and reduced cell growth. However as the complexity of oestrogen receptor function is increasingly revealed, particularly in terms of its mechanism of action and interactions with other signalling pathways, our understanding of Tamoxifen activity and the development of resistance against it has also expanded. Tamoxifen resistance may be either "de novo " (present prior to Tamoxifen treatment) or "acquired" during the course of treatment. Identifying the biological mechanisms behind Tamoxifen resistance is important particularly as increasing clinical trials evidence implies superiority of aromatase inhibitors over Tamoxifen. It is not currently clear whether this superiority is the case for all ER positive patients, or whether there is a particular group of patients resistant to Tamoxifen whose tumours may be sensitive to aromatase inhibitors. The HER family of tyrosine kinase receptors (HERl-4) initiate a complex signal transduction cascade modulating cell proliferation, survival, adhesion, migration and differentiation. We have postulated that cross talk between the HER family and the ER may underlie development of Tamoxifen resistance in breast cancer. We have used tissue microarray technology and immunohistochemistry in analysis of a retrospective database of 402 ER positive, Tamoxifen treated patients to test the hypothesis that overexpression of HER family members 1-3 is associated with phosphorylation of the ER and with clinical relapse on Tamoxifen ('Tamoxifen resistance'). We have demonstrated that HERl-3 (but not HER4) and PR status can identify time- dependent de novo Tamoxifen resistance, with risk declining markedly after 3 years of tamoxifen treatment. We also demonstrate for the first time in vivo expression of phosphorylated ERalpha at the cell membrane of breast cancer cells and have demonstrated a correlation between HERl-3 status and membranous phosphorylated ER. This supports recent reports of an interaction between membrane-bound ERα and the BDER family and its pathways and provides further evidence for the non-classical actions of the ERα at the membrane. We confirm previous reports that phosphorylated ERα in the nucleus is associated with higher ERα expression and a more differentiated phenotype suggesting that it acts as a marker of an intact, functional, ERα signalling pathway. Data presented here demonstrates the significant role played by HERl-3 in promoting Tamoxifen resistance in hormone responsive breast cancers. It also emphasises the different role of HER4 in this context. This work is particularly clinically relevant with recent trials suggesting that the apparent superiority of aromatase inhibitors over Tamoxifen may be linked to the expression of specific tumour markers. In fact our results parallel those from the ATAC and lES trials which suggest that, whilst PR negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no impact on response when given as delayed treatment to those who were disease free on Tamoxifen after 3 years. Taken together, these data strongly supports the conclusion that the predictive value of PR, and possibly HERl-3, expression is time dependent and identifies patients at high risk of de novo Tamoxifen resistance. The ability to select, at diagnosis, patients at high risk of early relapse on Tamoxifen could provide the opportunity to tailor their adjuvant therapy on an individual basis, either in terms of an aromatase inhibitor or by supplying them with a BDER family inhibitor such as Iressa or Herceptin to be used in conjunction with their endocrine treatment. There is some evidence that, in contrast to genomic activity, non-genomic ERα activity can be stimulated by SERMS such as Tamoxifen. Therefore Tamoxifen may be incapable of breaking (or even may stimulate) any cycle linking non-genomic and genomic ERα with the growth factor pathways. From our results, we speculate that membrane bound ERα, in conjunction with the BDER family, may be responsible for initiating tumour cell proliferation even in the presence of Tamoxifen resulting in de novo Tamoxifen resistance. These results have implications for establishing ERα status, particularly in the clinical diagnostic setting, as more detailed analysis in terms of location and function of the receptor may become the norm for diagnostic testing in the future. Further research is required to determine the mechanisms relating to Tamoxifen resistance particularly in regard to the nature of the interactions at the membrane between the ER and HER family. Testing these hypotheses in the context of the redesigned TEAM trial will provide a valuable insight into the most appropriate future therapeutic options for differing sets of breast cancer patients.