When Tumor Suppressor TGFβ Meets the HER2 (ERBB2) Oncogene

被引:0
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作者
Amy Chow
Carlos L. Arteaga
Shizhen Emily Wang
机构
[1] Beckman Research Institute of City of Hope,Division of Tumor Cell Biology, Department of Cancer Biology
[2] Cancer Biology Program,Departments of Medicine and Cancer Biology
[3] City of Hope Comprehensive Cancer Center,undefined
[4] Vanderbilt University School of Medicine,undefined
[5] Beckman Research Institute of City of Hope,undefined
关键词
TGFβ; HER2 (ERBB2); Breast cancer; Drug resistance;
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摘要
Despite its tumor suppressive role in normal mammary epithelial cells, TGFβ has been reported to promote the migration, invasion and survival in breast cancer cells overexpressing the HER2 (ERBB2; neu) oncogene, and to accelerate the metastasis of neu-induced mammary tumors in mice. A clearer understanding of the molecular mechanisms underlying the crosstalk between TGFβ and HER2 has started to emerge. In recent studies reviewed here, the synergistic effect of TGFβ and HER2 on tumor progression has been shown to likely be a combined result of two distinct features: (1) loss of TGFβ’s tumor suppressive effect through functional alterations in the anti-mitogenic effect of Smad-mediated transcription, and (2) gain of pro-survival and pro-migratory function through HER2-dependent mechanisms. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. Thus, the transformed cellular context imparted by constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, aborts the tumor suppressive role of TGFβ and facilitated the oncogenic role of this pathway. In turn, TGFβ potentiates oncogenic HER2 signaling by inducing shedding of the ERBB ligands and clustering of HER2 with integrins. Here we discuss recent studies examining Smad-dependent and -independent mechanisms of crosstalk between TGFβ and HER2. Therefore, blockade of TGFβ:HER2 crosstalk may suppress breast cancer progression and metastasis, and enhance the efficiency of conventional therapies in patients with HER2-overexpressing breast cancer.
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页码:81 / 88
页数:7
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