Breast cancer is the second leading cause of cancer-related deaths among women, with deaths occurring due to the metastatic spread of tumor cells to distant organs. Spread of cancer cells occurs via blood vessels or, particularly important for breast cancer, via the lymphatic system. Although tumor dissemination via the blood has been extensively studied, the mechanisms that lead to lymphatic dissemination are poorly understood. This proposal focuses on understanding a new mechanism of lymphangiogenesis and breast tumor metastatic spread, via control of VEGF-C levels by the Six1/Eya2 transcriptional complex. The hypothesis to be tested is that Six1 overexpression in breast cancers leads to upregulation of VEGF-C, resulting in increased lymphangiogenesis and enhancing the early stages of metastasis including lymphatic dissemination of tumor cells. The ability of Six1 to activate VEGF-C and stimulate lymphatic metastasis is dependent on its interaction with the Eya2 phosphatase co-factor, and on the enzymatic activity of Eya2. If this hypothesis is correct, it will provide important insights into the mechanism of breast cancer metastasis and provide a rationale for a new strategy to therapeutically target lymphatic metastasis by interfering with Six1/Eya2 function through the """"""""druggable"""""""" approaches of inhibiting Six1/Eya interaction and/or Eya2 phosphatase activity. To address this hypothesis, we will: 1) Test the hypothesis that VEGF-C is a direct transcriptional target of Six1/Eya2, and that Six1 and Eya2 correlate with VEGF-C and lymphangiogenesis in human breast cancer;2) Test the hypothesis that VEGF-C is a critical mediator of Six1-induced lymphangiogenesis and metastasis using in vivo mouse metastasis models;and 3) Test the hypothesis that Eya2 is required for Six1-induced lymphangiogenesis and metastasis in vivo, with a specific emphasis on the interaction between Six1 and Eya2, as well as the role of the Eya2 phosphatase activity. Targeting Six1/Eya2 has the potential to inhibit breast cancer both at early (studied in this proposal) and later stages of the disease. Due to the paucity of expression of the Six1/Eya2 developmental regulators in most normal adult tissues, and their re-expression in cancers, therapeutic agents targeting this complex should inhibit lymphangiogenesis and metastasis with limited side effects. Thus the Six1/Eya2 complex is an ideal breast cancer therapeutic target, and work within this proposal will lay the foundation for eventual targeting of the complex.
The vast majority of breast cancer related deaths occur due to the spread of tumor cells to distant organs, a spread that occurs via blood vessels or, particularly important for breast cancer, via the lymphatic system. Surprisingly, however, very little is known about the mechanism by which tumor cells promote new lymphatic vessel development (lymphangiogenesis) and lymphatic spread. This proposal focuses on understanding a new mechanism of lymphangiogenesis and breast tumor metastatic spread, via control of VEGF-C levels by the Six1/Eya2 complex, and it lays the foundation for the development of novel, anti-metastatic therapeutic agents that would target embryonic proteins that are re-expressed in cancers, thus conferring limited side effects while potently inhibiting breast cancer metastasis.
|Dimberg, Lina Y; Towers, Christina G; Behbakht, Kian et al. (2017) A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance. Mol Cancer Res 15:382-394|
|Blevins, Melanie A; Towers, Christina G; Patrick, Aaron N et al. (2015) The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets 19:213-25|
|Towers, Christina G; Guarnieri, Anna L; Micalizzi, Doug S et al. (2015) The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nat Commun 6:10077|
|Wang, Chu-An; Drasin, David; Pham, Catherine et al. (2014) Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression. Cancer Res 74:7357-70|
|Wang, Chu-An; Harrell, J Chuck; Iwanaga, Ritsuko et al. (2014) Vascular endothelial growth factor C promotes breast cancer progression via a novel antioxidant mechanism that involves regulation of superoxide dismutase 3. Breast Cancer Res 16:462|
|Patrick, Aaron N; Cabrera, Joshua H; Smith, Anna L et al. (2013) Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. Nat Struct Mol Biol 20:447-53|
|Farabaugh, S M; Micalizzi, D S; Jedlicka, P et al. (2012) Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-? signaling, epithelial-mesenchymal transition, and cancer stem cell properties. Oncogene 31:552-62|
|Wang, Chu-An; Jedlicka, Paul; Patrick, Aaron N et al. (2012) SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer. J Clin Invest 122:1895-906|
|Drasin, David J; Robin, Tyler P; Ford, Heide L (2011) Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity. Breast Cancer Res 13:226|
|Micalizzi, Douglas S; Wang, Chu-An; Farabaugh, Susan M et al. (2010) Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. Cancer Res 70:10371-80|
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