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Synergy between the erbB and transforming growth factor beta signaling networks: implications for molecular therapeutics in human neoplasia

The overexpression and aberrant function of the epidermal growth factor receptor (EGFR) (HER1, erbB1) and its ligands in several human carcinomas have provided a rationale for targeting this signaling network with novel treatment approaches. Based on the structure and function of the EGFR, two anti-receptor strategies have been developed. The first strategy uses humanized monoclonal antibodies generated against the receptor's ligand-binding, extracellular domain. These antibodies block binding of receptor-activating ligands and, in some cases, can induce receptor endocytosis and downregulation. The second approach uses small molecules that compete with ATP for binding to the receptor's kinase pocket, thus blocking receptor activation and the transduction of post-receptor signals. In addition, these are effective in blocking ligand-independent intracellular signals that laterally activate the receptor. Data will be presented in support of the merits of using antibodies and small molecules in combination. The transforming growth factor beta (TGF-β) signaling pathway is also associated with metastatic tumor progression. Antibodies against TGF-β ligands, small molecule inhibitors of the TGF-β type I receptor (Tβ RI) serine/threonine kinase, and soluble TβRII:Fc fusion proteins are anti-signaling approaches in development. Data suggest that both the erbB and TGF-β signaling networks can synergistically contribute to tumor progression. For example, signaling by the Ras/MAPK pathway, downstream erbB receptors, has been reported to abrogate the anti-proliferative effect of TGF-β in epithelial cells. Therefore, we have examined whether overexpression of HER2/neu (erbB2), a potent inducer of Ras/MAPK signaling, modifies the inhibitory effect of TGF-β against MCF-10A human breast epithelial cells. MCF-10A stably transfected with a HER2 expression vector retained TGF-β receptors. Exogenous TGF-β inhibited MCF-10A/HER2 cell proliferation and still induced both Smad2 translocation to the nucleus and pCAGA-Lux reporter activity. In wound closure and transwell assays, exogenous TGF-β induced lamellopodia and actin stress fiber formation and motility of MCF-10A/HER2 but not of control cells transfected with vector alone. These effects were blocked by addition of the phosphatidylinositol 3-kinase inhibitor LY294002, the p38Mapk inhibitor SB202190, and the MEK1/2 inhibitor U0126. The HER2 antibody Herceptin blocked TGF-β-induced motility but not Smad-dependent reporter activity. Infection with an adenovirus encoding a constitutively active Tβ RI mutant (T204D) induced motility of MCF-10A/HER2 but not control cells. In HER2-overexpressing cells, Rac1 and Pak1 were constitutively associated with HER2. TGF-β enhanced this association as well as MCF-10A/HER2 Rac1 activity as measured by Rac1 binding to a GST-Pak binding domain fusion protein. Thus, overexpression of HER2 unmasks the ability of TGF-β to induce epithelial cell motility. This effect is not limited to HER2 in that treatment of EGFR-amplified A431 squamous cancer cells with TGF-β also induces motility which is blocked by the EGFR tyrosine kinase inhibitor ZD1839. To follow these results, we have generated mouse mammary tumor virus (MMTV)/neu × MMTV/TGFβ 1S223/225 bigenic mice. TGFβ 1 delayed mammary ductal extension in the bigenics compared with MMTV/neu mice but mammary tumor latency was similar. Although the bigenic tumors were smaller and less proliferative, they exhibited a higher histological grade and were more metastatic than MMTV/neu tumors. Finally, TGF-β accelerated tumor cell intravasation in MMTV/neu × MMTV/TGFβ 1 bigenic mice compared with MMTV/neu mice. These data suggest, first, cooperation between the erbB receptor and TGF-β signaling in promoting the metastatic phenotype of human breast cancer cells. Second, they imply that combined inhibition of multiple signaling networks in human cancer cells might be required in order to meaningfully alter their natural progression.

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Arteaga, C. Synergy between the erbB and transforming growth factor beta signaling networks: implications for molecular therapeutics in human neoplasia. Breast Cancer Res 5 (Suppl 1), 26 (2003).

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