Breast cancer is the most common malignancy among western women. Although adjuvant and molecularly targeted therapies significantly improve patient survival, breast cancer metastasis remains incurable and is the main cause of morbidity and cancer death in women. Recent genome-wide analysis of human breast cancer identified EphA2 receptor tyrosine kinase as a promising target. We and others found that EphA2 is overexpressed in ~60% of human breast cancer specimens, including drug-resistant HER2 positive tumors and triple-negative/basal-like breast cancer, correlating with poor survival. Ablation of EphA2 in mice inhibited metastatic progression in the HER-dependent MMTV-Neu mammary tumor model. In contrast, expression of ephrin-A1, the prototypic ligand for EphA2, is frequently lost in lymph node metastasis patients and high levels of ephrin-A1 correlates with better survival in patients with metastatic disease, suggesting that ligand-dependent signaling inhibits EphA2-dependent tumor progression and metastatic spread. Therefore, we hypothesize that ephrin-A1 acts as a molecular switch, such that loss of ephrin converts EphA2 functions from tumor suppression to tumor promotion. We are poised to test this model in our newly generated ephrin-A1-null mouse model. In this proposal, we will test the inhibitory role of ephrin-A1 ligand in mammary tumor growth and metastasis in mice and its value as a biomarker for metastatic breast cancer, with the ultimate goal of developing ephrin-A1 as a new prognostic marker for predicting the relative risk of human breast cancer metastasis. We will also determine if EphA2 is required for tumor progression and metastasis induced by loss of ephrin-A1, using both a genetic approach and a selective EphA2 kinase inhibitor (Aim 1). As a first step in investigating the mechanism through which ephrin-A1 inhibits breast cancer progression, we discovered elevated fatty acid synthase (FASN) expression and lipid content, as well as increased glutaminolysis in ephrin-A1-null/MMTV-Neu tumors. Since lipid and glutamine metabolism contributes to breast cancer pathogenesis, we will determine if molecular regulation of lipogenesis and glutaminolysis by ephrin/Eph signaling contributes to growth and metastasis in vivo (Aim 2). Success of this project will not only elucidate the molecular mechanisms that control the switch between tumor promotion versus tumor suppression by EphA2 RTK, but also validate novel EphA2-targeting selective kinase inhibitors for treatment of breast cancer subtypes that are refractory to current therapies, such as triple-negative/basal-like breast cancer or HER2 positive cancers that developed resistance to anti-HER2 agents. In addition, this proposal addresses several areas emphasized in the NCI's """"""""provocative questions"""""""" in cancer biology, including """"""""oncogene addiction"""""""" and """"""""tumor metabolism/obesity's influences on cancer"""""""".
Breast cancer is the most common malignancy among western women. We recently discovered that a cell-surface molecule (EphA2) is required for tumor growth and metastasis in breast cancer, whereas another molecule that binds to EphA2, ephrin-A1, may inhibit EphA2 function and suppress tumor metastasis. Our goal of this project is to determine how ephrin-A1 inhibits breast cancer metastasis and to test new drugs targeting EphA2 in subtypes of breast cancer that are refractory to existing therapies.
|Kim, L C; Cook, R S; Chen, J (2017) mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene 36:2191-2201|
|Edwards, Deanna N; Ngwa, Verra M; Wang, Shan et al. (2017) The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ. Sci Signal 10:|
|Song, W; Hwang, Y; Youngblood, V M et al. (2017) Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers. Oncogene 36:5620-5630|
|Youngblood, Victoria M; Kim, Laura C; Edwards, Deanna N et al. (2016) The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer. Cancer Res 76:1825-36|
|Shiuan, Eileen; Chen, Jin (2016) Eph Receptor Tyrosine Kinases in Tumor Immunity. Cancer Res 76:6452-6457|
|Amato, Katherine R; Wang, Shan; Tan, Li et al. (2016) EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res 76:305-18|
|Fang, Wei Bin; Yao, Min; Jokar, Iman et al. (2015) The CCL2 chemokine is a negative regulator of autophagy and necrosis in luminal B breast cancer cells. Breast Cancer Res Treat 150:309-20|
|Chen, Jin; Song, Wenqiang; Amato, Katherine (2015) Eph receptor tyrosine kinases in cancer stem cells. Cytokine Growth Factor Rev 26:1-6|
|Wang, Shan; Amato, Katherine R; Song, Wenqiang et al. (2015) Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways. Mol Cell Biol 35:1299-313|
|Youngblood, Victoria; Wang, Shan; Song, Wenqiang et al. (2015) Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium. Mol Cancer Res 13:524-37|
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