Overexpression of the receptor tyrosine kinase HER2 (ErbB2) and activation of transforming growth factor ??(TGF?) signaling are both associated with progression of breast cancers to a more metastatic phenotype. Overexpression of the HER2 proto-oncogene is permissive for the tumor promoting effects of TGF?. The objective of this proposal is to study the reciprocal, temporal and spatial crosstalk between TGF? and HER2, which involves not only intra-/intercellular but also microenvironmental events. We hypothesize that in HER2-mediated transformation, TGF? can 1) dynamically modulate HER2 subcellular distribution and the repertoire of HER2 cellular substrates/signal transducers;2) regulate the magnitude and amplitude of HER2 signaling through the modulation of HER2 phosphorylation and cellular trafficking;3) modify the ECM and stroma to create a microenvironment that facilitates tumor growth and metastasis;and 4) attenuate the response of HER2-dependent cells to therapeutic inhibitors of HER2. Understanding the temporal and spatial features of the crosstalk between TGF? and HER2 signaling will disclose new therapeutic targets, as well as potentially allow the optimization of current therapeutic inhibitors of HER2. The results will also shed light on the perspective of a combined therapy against TGF? and HER2 in breast cancer patients. The following specific aims will be pursued.
Specific aim 1 : to determine whether activated TGF? receptors spatially and temporally modulate HER2 signaling in mammary epithelial cells and how TGF? -induced cytoskeleton remodeling affects HER2 distribution, trafficking and signaling.
Specific aim 2 : to determine whether the Rac/Pak pathway is required for the invasiveness and survival mediated by the interaction between HER2 and TGF?, whether HER2 is a substrate of Pak1 and whether HER2 colocalizes with Pak1 and active Rac1 in primary breast tumors.
Specific aim 3 : to determine whether TGF? and HER2 modify microenvironmental components by utilizing proteomic approaches and whether these contribute to tumorigenesis in mice.
Specific aim 4 : to determine whether activated TGF? signaling can confer resistance to therapeutic inhibitors of HER2 in mammary cancer cells and the role of PI3K and Rac/Pak pathways in TGF? -conferred resistance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Special Emphasis Panel (ZCA1-RTRB-A (O1))
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Snyderwine, Elizabeth G
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City of Hope/Beckman Research Institute
United States
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Tsuyada, Akihiro; Wang, Shizhen Emily (2013) Fibroblast-derived CCL2 induces cancer stem cells--response. Cancer Res 73:1032-3
Wang, Shizhen Emily; Lin, Ren-Jang (2013) MicroRNA and HER2-overexpressing cancer. Microrna 2:137-47
Tsuyada, Akihiro; Chow, Amy; Wu, Jun et al. (2012) CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res 72:2768-79
Chandra, Manasa; Zang, Shengbing; Li, Haiqing et al. (2012) Nuclear translocation of type I transforming growth factor ýý receptor confers a novel function in RNA processing. Mol Cell Biol 32:2183-95
Wang, Shizhen Emily (2011) The Functional Crosstalk between HER2 Tyrosine Kinase and TGF-? Signaling in Breast Cancer Malignancy. J Signal Transduct 2011:804236
Wang, Y; Yu, Y; Tsuyada, A et al. (2011) Transforming growth factor-? regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene 30:1470-80
Chow, Amy; Arteaga, Carlos L; Wang, Shizhen Emily (2011) When tumor suppressor TGF? meets the HER2 (ERBB2) oncogene. J Mammary Gland Biol Neoplasia 16:81-8
Yu, Yang; Wang, Yujun; Ren, Xiubao et al. (2010) Context-dependent bidirectional regulation of the MutS homolog 2 by transforming growth factor ? contributes to chemoresistance in breast cancer cells. Mol Cancer Res 8:1633-42
Wang, S E; Yu, Y; Criswell, T L et al. (2010) Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators. Oncogene 29:3335-48
Wang, Shizhen Emily; Hinow, Peter; Bryce, Nicole et al. (2009) A mathematical model quantifies proliferation and motility effects of TGF-? on cancer cells. Comput Math Methods Med 10:71-83

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