There is now substantial in vitro and in vivo experimental evidence revealing that the control of endocrine-resistant breast cancer growth is a multifaceted event, involving signalling through many different growth factor receptor tyrosine kinases which provide a complex network of interacting signal transduction pathways impinging on tumour proliferation and cell survival parameters (6, 7, and references therein). For example, several studies have established that the intracellular signalling pathways associated with oestrogen-receptor (ER) and IGF-1R action are highly interactive. As such, anti-hormonal drugs can exert their anti-oestrogenic activity through disruption of oestrogen/IGF-1R signalling cross-talk (6) in addition to their more classical effects of blockade of ER/oestrogen response element (ERE) signalling. It follows that the growth inhibitory properties of such drugs are thus a combination of anti-oestrogenic and anti-growth factor activities (8-10). Similarly, members of the EGFR family of receptors have a well-established role in acquired endocrine resistance: oestrogens suppress the transcription of both the EGFR and HER2 (7,11,12) in ER-positive breast cancer cell models in vitro (13,14) and, as might be predicted, anti-hormones such as tamoxifen are able to promote the expression of EGFR and HER2. This, in turn, can lead to the mitogen-activated protein kinase (MAPK)/ AKT-mediated activation of the ER and, as a consequence, increased production of key ER-regulated EGFR ligands such as transforming growth factor alpha (TGFa) and amphiregulin (15-17), thereby completing an autocrine signalling loop. These events subsequently provide an efficient mechanism to drive anti-hormone-resistant growth (18). Significantly, EGFR expression, kinase activity, and reactivation of ER incrementally increase during treatment, culminating in emergence of EGFR-mediated, ER-positive, acquired tamoxifen-resistant growth (15,19).
Tumour progression and spread requires a cell phenotype that displays altered biological activities other than simply deregulated proliferation, such as invasiveness and motility, and it has been speculated that the EGFR may play a role in this process. High levels of EGFR have been demonstrated in a number of aggressive tumour types including head and neck cancer, non-small-cell lung cancer, colorectal cancer, and ovarian tumours (7). Furthermore, elevated levels of EGFR correlate with increased invasiveness and metastasis and are associated with a poor clinical prognosis (11, 20, 21). Although expression of the EGFR protein may be increased in tumour tissue, it is likely that its activation state has a greater bearing on prognosis than expression of the protein alone. Constitutive activation of the EGFR may arise from autocrine production of EGFR ligands such as TGFa. Indeed, co-expression of EGFR and TGFa has been reported in non-small-cell lung cancers (22), prostate cancer (23), gastrointestinal tumours (24), and in invasive breast carcinomas, where expression is significantly correlated with poor patient prognosis (25). Signalling through the EGFR subsequently causes the simultaneous activation of multiple, functionally interlinked signalling pathways (which include the Grb2/Ras/MAPK pathway, phospholipid metabolism involving PLD, PLCy and PI3K and activation of the cytosolic Src family kinases (26, and references therein), ultimately promoting chemotaxis, migration, invasion, and the development of an aggressive cell phenotype (27-29). The critical role that the EGFR plays in malignant transformation and cancer progression has thus identified it as a promising therapeutic target. Current strategies that exist to target this molecule include various EGFR tyrosine kinase inhibitors such as gefitinib (30).
Our data has demonstrated that signalling through EGFR/HER2 also contributes to the increased migratory and invasive capacity of ERpositive, acquired tamoxifen-resistant (TAM-R) breast cancer cells in vitro. Such resistant cells highly express the EGFR and HER2 together with TGFa and amphiregulin (19). Inhibition of EGFR-mediated signalling in tamoxifen-resistant cells with gefitinib results in a reduction of the cells' migratory and invasive capacity in vitro (3). Furthermore, abrogation of HER2 function through use of Herceptin is also able to partially suppress these cells' aggressive phenotype (S. Hiscox, unpublished observations). Interestingly, time-lapse analysis of TAM-R cell movement has revealed that it occurs in a directional, rather than random, fashion (3). This phenomenon is reported to be controlled by localised EGFR signalling in other cell types including keratinocytes (31), fibroblasts (32), and human mammary epithelial cells (33) as a consequence of the asymmetrical activation of motility-promoting signalling pathways. Interestingly, expression of the EGFR on TAMR-R cells is observed to be predominantly located to the areas of the cells that displayed membrane activity (ruffles, lamellapodia) (3). Subsequently, gefitinib-treatment of TamR cells reduced the numbers of cells displaying membrane protrusions. Such observations have also been reported by others who have demonstrated the ability to block asymmetric EGFR expression using the EGFR inhibitor, PD158780 (31) and the invasion-suppressive effects of gefitinib in other cancer cell lines (34).
Modulation of EGFR activity using gefitinib has thus enabled us to establish the EGFR as a key player in the development of an enhanced metastatic phenotype in acquired tamoxifen-resistant breast cancer cells. Moreover, it demonstrates the potential of EGFR signalling inhibitors as a means of controlling this adverse phenotype.
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