Prolonged Growth Factor Signalling Contributes To The Invasive Phenotype Of Ernegative Breast Cancer Cells

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At its greatest extremes, it is believed that aberrant growth factor signalling may promote ER loss (58,59) and we now have evidence that it may also drive the very highly invasive phenotype associated with ER-

ER-negative cells. Certainly, a poor prognosis has invariably been reported for ER-negative clinical breast cancer (7,9,18,60,61), and invasiveness is substantial in de novo ER-negative breast cancer models such as MDA-MB-231 cells that exhibit extensive aberrant growth factor signalling. Moreover, our studies in ER-negative faslodex-resistant (FAS-R) cells also reveal that chronic exposure to more modest increases in EGFR/kinase/NFKB signalling during prolonged faslodex treatment can associate with morphological features characteristic of an epithelial-to-mesenchymal transition (EMT), together with very high levels of migratory and invasive activity in vitro alongside adaptive silencing of ER (4,59). In view of these observations, it is feasible that the chronic growth factor signalling that promotes ER negativity may culminate in parallel silencing of ER-regulated genes which play a central role in suppressing cellular invasion. In such cells, we are exploring whether there is a role for transcriptional silencing of any key anti-invasive genes and demonstrated that TIMP3 (tissue inhibitor of metalloproteinase 3) is partially methylated in ER-negative, FAS-R cells, an event that may contribute to their increased invasiveness. Interestingly, conventional RT-PCR analysis has also revealed further changes in TIMP and MMP expression, notably increased MMP2. This correlates with ability of broad-spectrum MMP inhibitors to suppress the invasive behaviour of FAS-R cells (62).

Using microarray analysis, we have also highlighted pro-invasive genes that are induced in FAS-R cells potentially arising as a consequence of chronically elevated growth factor signalling. Among these is the extracellular matrix protein vitronectin that is paralleled by substantially increased avP3 integrin, and also the cell surface receptor CD44, a glycoprotein involved in cell-cell and cell-matrix interactions (63,64). A number of splice variants of this molecule are expressed in such cells including CD44v3, which, interestingly, appears to have a close, inverse correlation with ER expression and provides a marker for poor prognosis in clinical breast cancer (65). Along with its role as a mediator of cellular adhesion, CD44 has been identified as an inducer of cell motility and activator of cell survival responses. Furthermore, overexpression of CD44 has been linked to the growth and spread of a range of different types of malignancies, particularly lymphomas.

Evidence suggests that antisence and antibody-mediated targeting of CD44 markedly reduces the malignant activities of tumours in vivo thus suggesting the therapeutic potential of anti-CD44 agents. Furthermore, because alternative splicing and post-translational modifications which generate the many different CD44 variants, some of which may be only associated with tumours, the production of anti-CD44 tumour-specific agents may be a realistic therapeutic approach.

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