Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer

in Endocrine-Related Cancer
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Stephen Hiscox
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L Morgan
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Tim Green
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Robert I Nicholson
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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.

Abstract

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

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 α (TGFα; 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

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

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

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 β-catenin and p120-catenin (p120CTN) 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

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

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

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.

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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  • Reynolds AB, Daniel JM, Mo YY, Wu J & Zhang Z 1996 The novel catenin p120cas binds classical cadherins and induces an unusual morphological phenotype in NIH3T3 fibroblasts. Experimental Cell Research 225 328–337.

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  • Ring A & Dowsett M 2004 Mechanisms of tamoxifen resistance. Endocrine-Related Cancer 11 643–658.

  • Roura S, Miravet S, Piedra J, Garcia de Herreros A & Dunach M 1999 Regulation of E-cadherin/Catenin association by tyrosine phosphorylation. Journal of Biological Chemistry 274 36734–36740.

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  • Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR & Parsons JT 1994 Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Molecular and Cellular Biology 14 1680–1688.

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  • Schlaepfer DD, Mitra SK & Ilic D 2004 Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochimica et Biophysica Acta 1692 77–102.

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  • Shupnik MA 2004 Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene 23 7979–7989.

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  • Slack JK, Adams RB, Rovin JD, Bissonette EA, Stoker CE & Parsons JT 2001 Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells. Oncogene 20 1152–1163.

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    • Export Citation
  • Tang CK, Perez C, Grunt T, Waibel C, Cho C & Lupu R 1996 Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Research 56 3350–3358.

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    • Export Citation
  • Thomas SM & Brugge JS 1997 Cellular functions regulated by Src family kinases. Annual Review of Cell and Developmental Biology 13 513–609.

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  • Thomas JW, Ellis B, Boerner RJ, Knight WB, White GC, II & Schaller MD 1998 SH2- and SH3-mediated interactions between focal adhesion kinase and Src. Journal of Biological Chemistry 273 577–583.

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  • Tovey S, Dunne B, Witton CJ, Forsyth A, Cooke TG & Bartlett JM 2005 Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Clinical Cancer Research 11 4835–4842.

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    • Export Citation
  • Tumbarello DA, Brown MC, Hetey SE & Turner CE 2005 Regulation of paxillin family members during epithelial-mesenchymal transformation: a putative role for paxillin delta. Journal of Cell Science 118 4849–4863.

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    • Export Citation
  • Wells A, Kassis J, Solava J, Turner T & Lauffenburger DA 2002 Growth factor-induced cell motility in tumor invasion. Acta Oncologica 41 124–130.

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  • Wheelock MJ & Johnson KR 2003 Cadherins as modulators of cellular phenotype. Annual Review of Cell and Developmental Biology 19 207–235.

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  • Wiener JR, Windham TC, Estrella VC, Parikh NU, Thall PF, Deavers MT, Bast RC, Mills GB & Gallick GE 2003 Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. Gynecologic Oncology 88 73–79.

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    • Export Citation
  • Wilson CA & Slamon DJ 2005 Evolving understanding of growth regulation in human breast cancer: interactions of the steroid and peptide growth regulatory pathways. Journal of the National Cancer Institute 97 1238–1239.

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    • Export Citation
  • Witters L, Engle L & Lipton A 2002 Restoration of estrogen responsiveness by blocking the HER-2/neu pathway. Oncology Reports 9 1163–1166.

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  • Xing Z, Chen HC, Nowlen JK, Taylor SJ, Shalloway D & Guan JL 1994 Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Molecular Biology of the Cell 5 413–421.

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  • Yap AS, Niessen CM & Gumbiner BM 1998 The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. Journal of Cell Biology 141 779–789.

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    • Export Citation

 

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  • Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA & Gallick GE 2002 Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 94 344–351.

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  • Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM & Osborne CK 1993 Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Research and Treatment 24 85–95.

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  • Biscardi JS, Ishizawar RC, Silva CM & Parsons SJ 2000 Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Research 2 203–210.

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  • Bjorge JD, Pang A & Fujita DJ 2000 Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. Journal of Biological Chemistry 275 41439–41446.

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  • Britton DJ, Hutcheson IR, Knowlden JM, Barrow D, Giles M, McClelland RA, Gee JM & Nicholson RI 2006 Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Research and Treatment 96 131–146.

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  • Brunton VG, MacPherson IR & Frame MC 2004 Cell adhesion receptors, tyrosine kinases and actin modulators: a complex three-way circuitry. Biochimica et Biophysica Acta 1692 121–144.

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  • Coluccia AM, Benati D, Dekhil H, De Filippo A, Lan C & Gambacorti-Passerini C 2006 SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Cancer Research 66 2279–2286.

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  • Frame MC 2002 Src in cancer: deregulation and consequences for cell behaviour. Biochimica et Biophysica Acta 1602 114–130.

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  • Gilmore AP & Romer LH 1996 Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Molecular Biology of the Cell 7 1209–1224.

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  • Gonzalez L, Manuel Garcia-Martinez J, Calcabrini A, Teresa Agullo M, Gamallo Amat C, Palacios Calvo J, Aranda A & Martin-Perez J 2006 Role of c-SRC in human MCF7 breast cancer cell tumorigenesis. Journal of Biological Chemistry 281 851–864.

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  • Guvakova MA & Surmacz E 1997 Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells. Cancer Research 57 2606–2610.

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  • Hennequin LF, Allen J, Curwen J, Fennell M, Green TP, Lambert-van der Brempt C, Morgentin R, Olivier R, Plé PA, Warin N et al.2006. The discovery of N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) a novel highly selective, orally available, dual-specific Src/abl kinase inhibitor. Journal of Medicinal Chemistry 2006 (in press).

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  • Hiscox S, Morgan L, Barrow D, Dutkowskil C, Wakeling A & Nicholson RI 2004 Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib (‘Iressa’, ZD1839). Clinical & Experimental Metastasis 21 201–212.

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  • Hiscox S, Morgan L, Green TP, Barrow D, Gee J & Nicholson RI 2005 Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Research and Treatment 1–12.

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  • Hiscox S, Jiang WG, Obermeier K, Taylor K, Morgan L, Burmi R, Barrow D & Nicholson RI 2006 Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. International Journal of Cancer 11897 290–301.

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  • Irby RB & Yeatman TJ 2000 Role of Src expression and activation in human cancer. Oncogene 19 5636–5642.

  • Irby RB & Yeatman TJ 2002 Increased Src activity disrupts cadherin/catenin-mediated homotypic adhesion in human colon cancer and transformed rodent cells. Cancer Research 62 2669–2674.

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  • Jackson JG, Yoneda T, Clark GM & Yee D 2000 Elevated levels of p66 Shc are found in breast cancer cell lines and primary tumors with high metastatic potential. Clinical Cancer Research 6 1135–1139.

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  • Johnson FM, Saigal B, Talpaz M & Donato NJ 2005 Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clinical Cancer Research 11 6924–6932.

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  • Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE & Nicholson RI 2004 Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocrine-Related Cancer 11 793–814.

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  • Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE & Nicholson RI 2003 Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144 1032–1044.

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  • Kruger JS & Reddy KB 2003 Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells. Molecular Cancer Research 1 801–809.

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  • Kurokawa H & Arteaga CL 2001 Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. Clinical Cancer Research 7 4436s–4442s (Discussion 4411s–4412s).

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  • Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT & Arteaga CL 2000 Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Research 60 5887–5894.

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  • Lilien J & Balsamo J 2005 The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. Current Opinion in Cell Biology 17 459–465.

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  • Mao W, Irby R, Coppola D, Fu L, Wloch M, Turner J, Yu H, Garcia R, Jove R & Yeatman TJ 1997 Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential. Oncogene 15 3083–3090.

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  • Masaki T, Okada M, Tokuda M, Shiratori Y, Hatase O, Shirai M, Nishioka M & Omata M 1999 Reduced C-terminal Src kinase (Csk) activities in hepatocellular carcinoma. Hepatology 29 379–384.

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  • Masaki T, Igarashi K, Tokuda M, Yukimasa S, Han F, Jin YJ, Li JQ, Yoneyama H, Uchida N, Fujita J et al.2003 pp60c-src activation in lung adenocarcinoma. European Journal of Cancer 39 1447–1455.

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  • McClelland RA, Barrow D, Madden TA, Dutkowski CM, Pamment J, Knowlden JM, Gee JM & Nicholson RI 2001 Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). Endocrinology 142 2776–2788.

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  • Moro L, Dolce L, Cabodi S, Bergatto E, Erba EB, Smeriglio M, Turco E, Retta SF, Giuffrida MG, Venturino M et al.2002 Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. Journal of Biological Chemistry 277 9405–9414.

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  • Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, Mirosevich J, Lee FY & Jove R 2005 Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Research 65 9185–9189.

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  • Nicholson RI, Hutcheson IR, Harper ME, Knowlden JM, Barrow D, McClelland RA, Jones HE, Wakeling AE & Gee JM 2002 Modulation of epidermal growth factor receptor in endocrine-resistant, estrogen-receptor-positive breast cancer. Annals of the New York Academy of Sciences 963 104–115.

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  • Nicholson RI, Staka C, Boyns F, Hutcheson IR & Gee JM 2004 Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy. Endocrine-Related Cancer 11 623–641.

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  • Nicholson RI, Hutcheson IR, Britton D, Knowlden JM, Jones HE, Harper ME, Hiscox SE, Barrow D & Gee JM 2005 Growth factor signalling networks in breast cancer and resistance to endocrine agents: new therapeutic strategies. Journal of Steroid Biochemistry and Molecular Biology 93 257–262.

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  • Nollet F, Berx G & van Roy F 1999 The role of the E-cadherin/catenin adhesion complex in the development and progression of cancer. Molecular Cell Biology Research Communications 2 77–85.

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  • Owen JD, Ruest PJ, Fry DW & Hanks SK 1999 Induced focal adhesion kinase (FAK) expression in FAK-null cells enhances cell spreading and migration requiring both auto- and activation loop phosphorylation sites and inhibits adhesion-dependent tyrosine phosphorylation of Pyk2. Molecular and Cellular Biology 19 4806–4818.

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  • Parisot JP, Hu XF, DeLuise M & Zalcberg JR 1999 Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line. British Journal of Cancer 79 693–700.

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  • Petit V, Boyer B, Lentz D, Turner CE, Thiery JP & Valles AM 2000 Phosphorylation of tyrosine residues 31 and 118 on paxillin regulates cell migration through an association with CRK in NBT-II cells. Journal of Cell Biology 148 957–970.

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  • Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, Gorman CM, Parker MG, Sliwkowski MX & Slamon DJ 1995 HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10 2435–2446.

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  • Reynolds AB, Daniel JM, Mo YY, Wu J & Zhang Z 1996 The novel catenin p120cas binds classical cadherins and induces an unusual morphological phenotype in NIH3T3 fibroblasts. Experimental Cell Research 225 328–337.

    • Search Google Scholar
    • Export Citation
  • Ring A & Dowsett M 2004 Mechanisms of tamoxifen resistance. Endocrine-Related Cancer 11 643–658.

  • Roura S, Miravet S, Piedra J, Garcia de Herreros A & Dunach M 1999 Regulation of E-cadherin/Catenin association by tyrosine phosphorylation. Journal of Biological Chemistry 274 36734–36740.

    • Search Google Scholar
    • Export Citation
  • Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR & Parsons JT 1994 Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Molecular and Cellular Biology 14 1680–1688.

    • Search Google Scholar
    • Export Citation
  • Schlaepfer DD, Mitra SK & Ilic D 2004 Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochimica et Biophysica Acta 1692 77–102.

    • Search Google Scholar
    • Export Citation
  • Shupnik MA 2004 Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene 23 7979–7989.

    • Search Google Scholar
    • Export Citation
  • Slack JK, Adams RB, Rovin JD, Bissonette EA, Stoker CE & Parsons JT 2001 Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells. Oncogene 20 1152–1163.

    • Search Google Scholar
    • Export Citation
  • Tang CK, Perez C, Grunt T, Waibel C, Cho C & Lupu R 1996 Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Research 56 3350–3358.

    • Search Google Scholar
    • Export Citation
  • Thomas SM & Brugge JS 1997 Cellular functions regulated by Src family kinases. Annual Review of Cell and Developmental Biology 13 513–609.

    • Search Google Scholar
    • Export Citation
  • Thomas JW, Ellis B, Boerner RJ, Knight WB, White GC, II & Schaller MD 1998 SH2- and SH3-mediated interactions between focal adhesion kinase and Src. Journal of Biological Chemistry 273 577–583.

    • Search Google Scholar
    • Export Citation
  • Tovey S, Dunne B, Witton CJ, Forsyth A, Cooke TG & Bartlett JM 2005 Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Clinical Cancer Research 11 4835–4842.

    • Search Google Scholar
    • Export Citation
  • Tumbarello DA, Brown MC, Hetey SE & Turner CE 2005 Regulation of paxillin family members during epithelial-mesenchymal transformation: a putative role for paxillin delta. Journal of Cell Science 118 4849–4863.

    • Search Google Scholar
    • Export Citation
  • Wells A, Kassis J, Solava J, Turner T & Lauffenburger DA 2002 Growth factor-induced cell motility in tumor invasion. Acta Oncologica 41 124–130.

    • Search Google Scholar
    • Export Citation
  • Wheelock MJ & Johnson KR 2003 Cadherins as modulators of cellular phenotype. Annual Review of Cell and Developmental Biology 19 207–235.

    • Search Google Scholar
    • Export Citation
  • Wiener JR, Windham TC, Estrella VC, Parikh NU, Thall PF, Deavers MT, Bast RC, Mills GB & Gallick GE 2003 Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. Gynecologic Oncology 88 73–79.

    • Search Google Scholar
    • Export Citation
  • Wilson CA & Slamon DJ 2005 Evolving understanding of growth regulation in human breast cancer: interactions of the steroid and peptide growth regulatory pathways. Journal of the National Cancer Institute 97 1238–1239.

    • Search Google Scholar
    • Export Citation
  • Witters L, Engle L & Lipton A 2002 Restoration of estrogen responsiveness by blocking the HER-2/neu pathway. Oncology Reports 9 1163–1166.

    • Search Google Scholar
    • Export Citation
  • Xing Z, Chen HC, Nowlen JK, Taylor SJ, Shalloway D & Guan JL 1994 Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Molecular Biology of the Cell 5 413–421.

    • Search Google Scholar
    • Export Citation
  • Yap AS, Niessen CM & Gumbiner BM 1998 The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. Journal of Cell Biology 141 779–789.

    • Search Google Scholar
    • Export Citation