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When Tumor Suppressor TGFβ Meets the HER2 (ERBB2) Oncogene

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

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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Abbreviations

EGFR:

Epidermal growth factor receptor

ERBB:

Erythroblastic leukemia viral oncogene homolog

ERK:

Extracellular signal-regulated kinase

FAK:

Focal adhesion kinase

HER2:

Human epidermal growth factor receptor 2

JNK:

C-Jun NH2-terminal kinase

MAPK:

Mitogen-activated protein kinase

MMR:

DNA mismatch repair

MSH2:

mutS homolog 2

PI3K:

Phosphatidylinositol-3 kinase

RTK:

Receptor tyrosine kinase

SBE:

Smad binding element

TGFβ:

Transforming growth factor β

VEGF:

Vascular endothelial growth factor

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Acknowledgements

This review article was supported by NCI K99/R00 CA125892 (SEW).

Author information

Authors and Affiliations

  1. Division of Tumor Cell Biology, Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Amy Chow & Shizhen Emily Wang

  2. Cancer Biology Program, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Shizhen Emily Wang

  3. Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Carlos L. Arteaga

  4. Beckman Research Institute of City of Hope, KCRB Room 2007, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Shizhen Emily Wang

Authors
  1. Amy Chow
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  2. Carlos L. Arteaga
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  3. Shizhen Emily Wang
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Correspondence to Shizhen Emily Wang.

Additional information

Financial Support: NCI K99/R00 CA125892 (SEW)

Figure 2: Copyright © American Society for Microbiology [Molecular and Cellular Biology, 2008, Vol. 28: 5605–20, doi:10.1128/MCB.00787-08]

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Chow, A., Arteaga, C.L. & Wang, S.E. When Tumor Suppressor TGFβ Meets the HER2 (ERBB2) Oncogene. J Mammary Gland Biol Neoplasia 16, 81–88 (2011). https://doi.org/10.1007/s10911-011-9206-4

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  • DOI: https://doi.org/10.1007/s10911-011-9206-4

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