**6. Summary**

The persistent problem of drug resistance and in particular the therapeutic failure of endocrine agents presents serious therapeutic issues especially in view of the success of this type of intervention in a significantly large proportion of women with breast cancer. Many studies have focused on elucidating the mechanisms responsible for *de novo* and *acquired* independence from estrogen. Consensus of opinion favours the view that signaling pathways mediated through a variety of peptide growth factors is largely responsible for the aggressive proliferation of tumours that have ceased to depend upon the ER, although no single unifying or even major factor has been identified. Somewhat in parallel, the last few years have witnessed an increasing number of reports describing the relatively recently recognized phenomenon of EMT, highlighting its similarity to the events leading to tumour invasion and vascular dissemination. Many of the key mediators of EMT particularly the transcriptional repression of E-cadherin by SNAIL appear to be critical steps in tumour progression. The association of mesenchymal-like features such as cadherin switching, loss of adhesion proteins and CD24, increased vimentin and fibronectin, with ER-ve tumours, have been sporadically, almost anecdotally reported in the literature over the last decade or more. We have now found evidence to show that the acquisition of endocrine independence, due to induced ER loss, by previously ER+ breast cancer cells, is accompanied by all the hallmark features of EMT. Although it is still far from clear whether the two processes are occurring side by side or whether either is causal of the other, it seems reasonable to conclude that loss of ER can directly trigger EMT. It remains to be seen whether restoration of ER in the trans-differentiated cells can reverse EMT and allow the cells to regain estrogen dependence.
