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Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, King Edward VII Avenue, Cardiff, Wales CF10 3XF, UK
¹ AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK

(Requests for offprints should be addressed to S Hiscox; Email: hiscoxse1{at}cf.ac.uk)

This paper was presented at the 2nd Tenovus/AstraZeneca Workshop, Cardiff (2006). AstraZeneca supported the meeting and the Welsh School of Pharmacy, Cardiff University has supported the publication of these proceedings.

	Abstract

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
Endocrine therapy is the treatment of choice in hormone receptor-positive breast cancer. However, the effectiveness of anti-hormone drugs, such as tamoxifen, is limited because of the development of resistance, ultimately leading to disease progression and patient mortality. Using in vitro cell models of anti-hormone resistance, we have previously demonstrated that altered growth factor signalling contributes to an endocrine insensitive phenotype. Significantly, our recent studies have revealed that the acquisition of endocrine resistance in breast cancer is accompanied by a greatly enhanced migratory and invasive phenotype. Furthermore, therapeutic intervention using anti-growth factor monotherapies, despite an initial growth suppressive phase, again results in the development of a resistant state and a further augmentation of their invasive phenotype.

Using the dual specific Src/Abl kinase inhibitor, AZD0530, we have highlighted a central role for Src kinase in promoting the invasive phenotype that accompanies both anti-hormone and anti-growth factor resistance. Importantly, the use of Src inhibitors in combination with anti-growth factor therapies appears to be additive, producing a marked inhibitory effect on cell growth, migration and invasion and ultimately prevents the emergence of a resistant phenotype. These observations suggest that the inhibition of Src activity may present a novel therapeutic intervention strategy, particularly when used as an adjuvant in endocrine-resistant breast disease, with the potential to delay or prevent the acquisition of subsequent resistance to anti-growth factor therapies.

	Introduction

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
Despite the success of endocrine therapies in the treatment of oestrogen receptor (ER)-positive breast disease, a significant proportion of these cancers will develop resistance after an initial responsive phase, leading to disease relapse and patient mortality (Ring & Dowsett 2004). Therefore, the phenomenon of acquired resistance to anti-hormones, such as tamoxifen, presents a significant problem in the management of breast cancer patients.

Although presently poorly understood, the molecular mechanisms which underlie acquired resistance are likely to involve crosstalk between the ER and the growth factor receptor signalling pathways, resulting in a ligand-independent activation of the ER and the sustained cellular growth (Nicholson et al. 2004, Wilson & Slamon 2005, Gee et al. 2005, Britton et al. 2006). The role of the growth factor signalling in endocrine resistance has gained significant attention over the past decade and there is now compelling evidence which suggests that the inappropriate activation of growth factor signalling cascades can readily promote anti-hormone failure in breast cancer cells. Indeed, the epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor (TGF; McClelland et al. 2001, Knowlden et al. 2003, Arpino et al. 2004, Nicholson et al. 2004), HER2 (Benz et al. 1993, Kurokawa et al. 2000, Kurokawa & Arteaga 2001), HER3 and HER4 (Pietras et al. 1995, Tovey et al. 2005) and the insulin-like growth factor-I receptor (IGF-IR) along with its ligands, IGF-I and IGF-II (Guvakova & Surmacz 1997, Parisot et al. 1999), have been suggested to play a central role in mediating an endocrine-resistant state in some situations. Studies using breast cancer cells engineered to overexpress growth factors and/or their ligands have revealed that enhanced growth factor signalling can induce cellular migration and invasion (Tang et al. 1996, Wells et al. 2002, Kruger & Reddy 2003). Therefore, it follows that tamoxifen-resistant tumour cells expressing altered growth factors/growth factor receptors are more likely to exhibit an invasive phenotype.

Importantly, evidence is emerging which reveals that the development of endocrine resistance in breast cancer cells not only results in oestrogen-independent growth (Knowlden et al. 2003) but also is accompanied by altered cell–cell and cell–matrix adhesive interactions which promote a migratory and invasive phenotype in vitro (Hiscox et al. 2004, 2006, S Hiscox, L Morgan, NJ Jordan, TP Green & RI Nicholson, unpublished observations). Clearly, these observations suggest that the acquisition of a more aggressive behaviour in vivo is likely to favour the dissemination of tumour cells from the primary tumour and thus promote disease spread. Despite the significance of such findings, little is known about the molecular changes which precipitate an aggressive phenotype during the acquisition of endocrine resistance. In endocrine-resistant breast cancer cells, the presence of elevated growth factor receptor activity may impinge upon multiple intracellular signalling pathways promoting cellular growth, morphological changes and enhanced migration/invasive abilities. However, although therapies targeting the EGFR/HER2 pathway can eliminate the agonistic effect of tamoxifen and restore its anti-tumour activity (Nicholson et al. 2002, 2005, Witters et al. 2002), they have only a modest effect on the cells’ invasive phenotype; for example, in tamoxifen-resistant MCF7-derived cells, which overexpress activated EGFR/HER2, the anti-EGFR inhibitor, gefitinib, is only able to partially reduce their migratory and invasive capacity (Hiscox et al. 2004) and a similar case is seen with blockade of HER2 signalling (S Hiscox, unpublished observations). Therefore, these data suggest that an EGFR/HER2-driven input contributes to, but is not essential for, their invasive in vitro phenotype. Significantly, these anti-growth factor therapies are not spared the problem of resistance; chronic exposure of tamoxifen-resistant breast cancer cells to anti-growth factor monotherapies, such as gefitinib, results in the development of a further resistant state, with these now ‘dually resistant’ cells (insensitive to both anti-hormones and anti-growth factors) utilizing the IGF-IR signalling pathway and having an even greater invasive capacity than their tamoxifen-resistant counterparts (Jones et al. 2004). Therefore, it is likely that therapies targeting individual growth factor receptors will prove unsuccessful due to the tumour cells’ ability to ‘switch’ between growth factor receptor pathways and circumnavigate these inhibitors, resulting in further resistant phenotypes.

Recently, we have identified that the acquisition of resistance to both anti-hormones and anti-growth factors in breast cancer cells is accompanied by a significant elevation in Src kinase activity (Hiscox et al. 2005). In this paper, we discuss the consequences of increased Src activity for the development of an aggressive, invasive cell phenotype and demonstrate its potential as a therapeutic target for anti-invasive therapies. Furthermore, our recent findings suggest the potential benefits of targeting Src kinase, alongside existing anti-hormone and anti-growth factor therapies, for an improved anti-tumour response.

	Src kinase and cancer

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
Src is a 60 kDa non-receptor tyrosine kinase first identified as the transforming product (v-Src) of the oncogenic Rous sarcoma retrovirus and belongs to a family of tyrosine kinases of which there are currently nine identified members (reviewed in Thomas & Brugge 1997). With the exception of the widely expressed Src, Fyn and Yes, all other Src family kinases exhibit tissue-restricted expression. However, despite the ubiquitous presence of Src, Fyn and Yes, it is Src that is mostly associated with tumour progression and is the subject of this discussion.

Src kinase interacts with a diverse array of molecules, including growth factor receptors and cell–cell adhesion receptors, integrins and steroid hormone receptors (Biscardi et al. 2000, Irby & Yeatman 2000, Moro et al. 2002, Brunton et al. 2004, Shupnik 2004). Therefore, the biological consequences of Src activation are many and can include proliferation, survival, differentiation, migration and invasion in both normal and transformed cells (reviewed in Frame 2002). In the course of our studies to elucidate the mechanisms responsible for the invasive phenotype which accompanies anti-hormone resistance in breast cancer cells, we have identified that Src kinase activity (Src phosphorylated at Y419) is significantly enhanced (up to 20-fold) in a number of in vitro models of endocrine and anti-growth factor resistance, an effect which is independent of Src gene or protein level (Hiscox et al. 2005). Compared with adjacent normal tissues, elevated Src expression and/or activity has been reported in a wide range of tumour types, including breast cancer and in many of these tissues, an increase in Src activity correlates with disease stage or malignant potential (Aligayer et al. 2002, Masaki et al. 2003, Wiener et al. 2003). Furthermore, tumour cell lines possessing elevated Src activity are often highly metastatic, displaying an increased capacity for migration and invasion in vitro (Mao et al. 1997, Jackson et al. 2000, Slack et al. 2001, Irby & Yeatman 2002), further linking Src to tumour progression. Our findings that Src activity is significantly elevated in anti-hormone-resistant breast cancer cells suggest a potential causative factor for their aggressive phenotype. This is indeed the case as inhibition of Src activity using the dual Src/Abl inhibitor, AZD0530 (Hennequin et al. 2006) abrogates invasion and migration in anti-hormone-resistant and anti-growth factor-resistant cells (Hiscox et al. 2005).

It is presently unclear as to the mechanism by which Src activity is elevated in anti-hormone-resistant cells. Src may be activated through several mechanisms, but particularly through (i) alterations in the activity of regulatory phosphatases/kinases which control the phosphorylation of Src at positive- and negative-regulatory sites (Masaki et al. 1999, Bjorge et al. 2000), (ii) activation of growth factor signalling pathways (Biscardi et al. 2000) and (iii) through the displacement of negative-regulatory intramolecular SH-binding interactions within the Src protein itself through its binding to high-affinity substrates which may include growth factor receptors (Thomas et al. 1998, Belsches-Jablonski et al. 2001). In endocrine-resistant breast cancer cells, the level and/or activity of two major molecular regulators of Src kinase, protein tyrosine phosphatase 1B (PTP1B) and Csk, appear to remain unchanged (L Morgan, unpublished observations). Additionally, although these cells have shown elevated expression of growth factor receptors of the EGFR family, inhibition of EGFR or HER2 activity with gefitinib and herceptin respectively, only partially reduce Src activity. Taken together, these observations suggest that the increase in Src activity observed in anti-hormone resistance is likely to arise from multiple causes, including alterations in one or more of the regulatory elements outlined above and attempts are presently underway to determine the mechanism of Src hyperactivation in these cells.

	Promotion of an aggressive cell phenotype: the role of Src

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
As mentioned previously, elevated Src activity in tumour tissue and cell lines is associated with metastatic disease and an invasive cell phenotype. Given its contribution to these processes, there is presently much interest in Src as a therapeutic target; indeed, a number of recent studies have demonstrated that pharmacological targeting of Src kinase in other cancer cell types, including prostate (Nam et al. 2005) and non-small cell lung cancer (NSCLC; Johnson et al. 2005) can significantly suppress their migratory and invasive capacity.

Much evidence now demonstrates that Src may promote a migratory/invasive phenotype through its ability to modulate both cell–cell and cell–matrix adhesive interactions in tumour cells, the result of which is to promote a migratory phenotype in vitro which may thus favour tumour metastasis in vivo.

	Src weakens intercellular adhesion through modulation of cadherin/catenins

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
Intercellular adhesion in epithelial tumour cells is regulated primarily by E-cadherin and its associated intracellular catenin proteins which act to tether cadherins to the cell cytoskeleton (Wheelock & Johnson 2003). Together these molecular components form the adherens junction (AJ). The presence and correct functioning of AJs is integral to the maintenance of strong cell–cell adhesion and is paramount to ensure cell and tissue morphology and structure. Furthermore, many studies have demonstrated that the AJ may function as an actual suppressor of tumour invasion (Yap et al. 1998, Nollet et al. 1999).

Several AJ components, including ß-catenin and p120-catenin (p120^CTN) are direct Src substrates or are known to be downstream elements of Src-involved pathways, phosphorylated in a Src-dependent manner (Reynolds et al. 1996, Coluccia et al. 2006). Phosphorylation of these proteins can result in E-cadherin downregulation and/or loss of the linkage between cadherins and the cytoskeleton, promoting disruption of cell–cell contacts and contributing to increased cell migration (Roura et al. 1999, Lilien & Balsamo 2005, Coluccia et al. 2006). Tamoxifen-resistant breast cancer cells, which have elevated Src activity, display poor cell–cell contacts when grown in culture in vitro (Hiscox et al. 2006). Inhibition of Src phosphorylation in these cells using the Src kinase inhibitor, AZD0530, restores cell–cell contacts and results in reorganisation of the cells into tightly packed epithelial cell colonies similar to that of their parental, endocrine-sensitive cells. Underlying this phenomenon is likely to be a reversal of the Src-dependent increase in catenin phosphorylation since in anti-hormone-resistant cells, catenin phosphorylation is elevated as a consequence of elevated Src activity.

	Src modulates cell–matrix attachment through modulation of focal adhesion turnover

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
In addition to its role as a mediator of intercellular adhesion, Src is intimately linked with the complex intercellular adhesion machinery which regulates cell attachment to matrix and thus influences cell migration (see Brunton et al. 2004 for a review).

Cell surface integrin receptors bind to protein components of the extracellular matrix (ECM), providing a physical link between the ECM and the internal actin cytoskeleton of the cells, allowing cells to sense their surrounding environment. Integrin engagement with ECM proteins results in the formation of focal adhesions (FAs), sites of signalling at the cell periphery which contain many FA-associated signalling proteins, including focal adhesion kinase (FAK). Upon integrin engagement, FAK is phosphorylated at Y397 (Schaller et al. 1994), permitting Src binding and the subsequent phosphorylation of FAK at additional residues, including Y861 and Y925 (Xing et al. 1994, Maa & Leu 1998). This creates further binding sites on FAK which facilitate its interaction with several other focal adhesion-associated substrates, including paxillin (Schlaepfer et al. 2004). The net effect of these interactions is to enhance FAK activity and link FAK to multiple internal signalling pathways which are involved in the modulation of cell morphology, migration and invasion through remodelling of the actin cytoskeleton (Petit et al. 2000). Indeed, FAK, Src and paxillin have been considered to act together as a functional unit in which all components must be present to achieve optimal cell–matrix adhesion.

In endocrine-resistant breast cancer cells displaying increased Src kinase activity, the activity of FAK is elevated at certain residues independent of FAK expression (S Hiscox, L Morgan, NJ Jordan, TP Green & RI Nicholson, unpublished observations). Furthermore, we have demonstrated that the inhibition of the migratory and invasive capacity of endocrine-resistant breast cancer cells by AZD0530 may be further explained by the fact that inhibition of Src activity results in loss of FAK and paxillin phosphorylation in these cells (Hiscox et al. 2005). Suppression of paxillin phosphorylation or inhibition of FAK activity have previously been demonstrated to inhibit cell migration in vitro (Gilmore & Romer 1996, Owen et al. 1999, Tumbarello et al. 2005). Moreover, their activation involves Src, as demonstrated by the suppression of both FAK and paxillin phosphorylation following the expression of dominant-negative Src in breast cancer cells (Gonzalez et al. 2006), an event which leads to reduced attachment to matrix and migration. Interestingly, inhibition of Src activity in anti-hormone-resistant breast cancer cells induces a change in the appearance of focal adhesion structures, promoting their elongation (Hiscox et al. 2005). Similar observations have been reported in embryonic fibroblasts engineered to express a temperature-sensitive kinase-inactive Src where alterations in temperature which favoured mutant Src expression produced cells in which the FAs were significantly greater in size (Fincham & Frame 1998). This elongation of FAs may be indicative of deregulated FA turnover or an enhancement of FA ‘strength’ which would present the cell with a barrier to motility and invasion. Therefore, these observations suggest that the observed loss of motility and invasiveness in Src-inhibited cells arises in part from modification of the activity of FAK/paxillin and subsequent deregulation of focal adhesion turnover.

	Src inhibition in combination with anti-growth factors – novel therapeutic strategies

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
As previously discussed, the overexpression and/or elevated activity of growth factor receptors, particularly those of the EGFR family, is a phenomenon accompanying the acquisition of endocrine resistance. Indeed, tamoxifen-resistant MCF7 cells have elevated levels of activated EGFR and are more sensitive to the EGFR inhibitor, gefitinib, than are their endocrine-responsive counterparts (Knowlden et al. 2003). In these cells, Src kinase activity is also elevated. However, whereas gefitinib is effective at reducing cell growth, it only partially suppresses their invasive phenotype (Hiscox et al. 2004). Conversely, inhibition of Src kinase in these cells, while having only a modest inhibitory effect on their growth rate, prevents their migratory and invasive capacity (Hiscox et al. 2005). These observations suggest that the simultaneous inhibition of Src activity alongside anti-growth factor therapy may produce a combined effect in endocrine-resistant cancers exhibit overexpression of growth factor receptors. Our data suggest this to be the case, as combining the Src inhibitor, AZD0530, with gefitinib in tamoxifen-resistant MCF7 cells is additive towards the inhibition of cell growth, migration and invasion when compared with either agent alone (Hiscox et al. 2005). Furthermore, we have recently observed that the combined action of AZD0530 and gefitinib in these cells prevents the emergence of a further highly invasive, gefitinib-resistant state. The observation that this type of treatment rationale can produce an additive effect, preventing the emergence of an aggressive, resistant phenotype, suggests that it may also be of use in the prevention of acquired resistance to anti-hormones. Indeed, early data from our present studies are encouraging in this respect, demonstrating an additive effect on the suppression of acquired endocrine resistance when using anti-hormone and Src inhibition in combination in vitro.

	Conclusions and future perspectives

Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
Deregulated Src activity frequently occurs in solid tumours where it is associated with advanced disease stage and metastatic potential. In such cancers, Src may contribute to an aggressive tumour cell phenotype through modulation of cell–cell and cell–matrix interactions. Our data suggest that Src appears to play a fundamental role in both anti-hormone and anti-growth factor resistance, where it can drive the development of an aggressive phenotype in vitro. Although it may not be possible to predict which growth factor-signalling pathway will be utilised to sustain cellular growth in the presence of anti-hormone and/or anti-growth factor therapy, the ability to inhibit molecular components common to multiple growth factor-signalling pathways, such as Src, in combination with anti-hormone or anti-growth factor therapies appears to be successful strategy to prevent acquired resistance in breast cancer.

	Acknowledgements

 
The authors would like to thank staff of the Tenovus tissue culture unit for their contribution to this work.

	Funding

S Hiscox and R I Nicholson are in receipt of a research grant from AstraZeneca. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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Top Abstract Introduction Src kinase and cancer Promotion of an aggressive... Src weakens intercellular... Src modulates cell-matrix... Src inhibition in combination... Conclusions and future... References

 
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