Brk is coamplified with ErbB2 to promote proliferation in breast cancer

Abstract

Amplification of the receptor tyrosine kinase ErbB2 is frequently observed in breast cancer. Amplification of erbB2 is also associated with multiple genomic gains and losses; however, the importance of these associated changes is largely unknown. We demonstrate that Brk, a cytoplasmic tyrosine kinase, is coamplified and coexpressed with ErbB2 in human breast cancers. ErbB2 interacts with Brk and increases its intrinsic kinase activity. Expression of Brk enhances the ErbB2-induced activation of Ras/MAPK signaling and cyclin E/cdk2 activity to induce cell proliferation of mammary 3-dimensional acini in culture. In a murine model of breast cancer, expression of Brk was found to shorten the latency of ErbB2-induced tumors by promoting cell proliferation, with no effect on protection from apoptosis. Furthermore, overexpression of Brk conferred resistance to the ability of Lapatinib, an ErbB2 kinase inhibitor, to inhibit ErbB2-induced proliferation. Thus, we identified Brk as a drug target for ErbB2-positive cancers.amplification ͉ lapatinib ͉ tumorigenesis E rbB2 belongs to the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (1). Amplification of erbB2 occurs in approximately 25% of breast cancers and is correlated with poor clinical outcomes (2). Although ErbB2 is not activated by direct binding of a soluble ligand, it is activated by ligand-induced formation of heterodimers with other EGFR family members, namely, EGFR/ErbB1, ErbB3, and ErbB4. Overexpression of ErbB2 can also result in ligand-independent receptor homodimerization and activation (1, 3). Overexpression of neu (the murine homologue of human erbB2) under the control of mouse mammary tumor virus (MMTV) long terminal repeat (LTR) results in mammary tumorigenesis (4), suggesting that erbB2 can initiate tumorigenesis in vivo.ErbB2 is a drug target for human breast cancer. A humanized monoclonal antibody against the extracellular domain of ErbB2, Herceptin, in combination with chemotherapy, is used to treat patients expressing high levels of ErbB2 (5). In patients who respond to the treatment, Herceptin can delay mortality anywhere between 9 months and 3 years (5). However, almost 50% of patients with tumors that contain erbB2 amplification do not respond to Herceptin (6), and those who do respond develop resistance to the drug, highlighting the need for better options to treat patients with ErbB2-positive cancers. A better understanding of the ErbB2 signaling pathway can identify novel targets for combination therapy that will significantly aid our ability to treat patients with ErbB2-amplified breast cancers.Members of the ErbB2 signaling pathway can also be coamplified with ErbB2 in breast cancer (7-10). For example, Grb7, a Src homology domain (SH2) containing an adaptor molecule that associates with ErbB2 and amplifies signaling by ErbB2, is a component of the ErbB2 amplicon (10). In addition to the erbB2 amplicon, erbB2-amplified tumors also are characterized by several gains and losses located elsewhere in the genome (7,8)....

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

“…Levels of BRK are low in normal tissues, where its expression is restricted to differentiating epithelial cells (34,35); however, its expression is up-regulated in a variety of tumors, particularly breast and ovary, primarily at a transcriptional or post-tran- scriptional level, rather than by mutation (36). In fact, BRK is highly expressed in Ͼ80% of breast cancers (31,37,38) and has been suggested as a potential therapeutic target (39,40).…”

“…BRK also affects the function of other EGFR family members. HER2 (40,48), and complex formation between the BRK and HER2 proteins, which promotes HER2 signaling in breast cancer (31). The effects of BRK are not restricted to the EGFR family; for example, it is also activated downstream of MET, which is associated with increased invasiveness of breast cancer cell lines (49).…”

PTK6 Inhibits Down-regulation of EGF Receptor through Phosphorylation of ARAP1

“…PTK6 and insulin receptor substrate 4 interact through the SH3 and SH2 domains of PTK6 after stimulation by IGF-1, and this interaction increases the tyrosine phosphorylation and enzymatic activity of PTK6 (23). PTK6 also interacts with ErbB2 and enhances ErbB2-induced cell proliferation by inducing prolonged activation of the Ras/MAP kinase pathway and activation of the cyclin E/cdk2 complex (24). Furthermore, substrates of PTK6, including STAT3, STAT5b, kinesin-associated protein 3A, and p190Rho-GAP, stimulate cellular proliferation (25)(26)(27)(28)(29).…”

Interactions of STAP-2 with BRK and STAT3/5 in Breast Cancer Cells

“…These observations suggest that BRK is involved in signaling induced by members of the EGFR family (Ostrander et al, 2007). Notably, BRK interacts with additional ErbB family members (ErbB2, ErbB3, and ErbB4) as well as EGFR (ErbB1) (Kamalati et al, 1996;Aubele et al, 2007;Xiang et al, 2008). BRK is co-amplified with ErbB2 to promote proliferation and confer resistance to lapatinib, an ErbB2 kinase inhibitor in breast cancer (Xiang et al, 2008), suggesting that BRK is a potential target in ErbB2-positive breast cancer.…”

“…Notably, BRK interacts with additional ErbB family members (ErbB2, ErbB3, and ErbB4) as well as EGFR (ErbB1) (Kamalati et al, 1996;Aubele et al, 2007;Xiang et al, 2008). BRK is co-amplified with ErbB2 to promote proliferation and confer resistance to lapatinib, an ErbB2 kinase inhibitor in breast cancer (Xiang et al, 2008), suggesting that BRK is a potential target in ErbB2-positive breast cancer. As mentioned above, BRK kinase activity is promoted by ligands for the ErbB receptor, such as EGF and heregulin.…”