These studies aim to define at a higher level of resolution the mechanism by whch the Retinal Determination Gene Network or pathway (RDGN) governs breast cancer onset and progression. Hyperactive growth factor receptor signaling remains active in many tumors that resist current therapies. The Drosophila dac gene was cloned as a dominant inhibitor of the hyperactive EGFR (Elipse). DACH1 reversed the transformed phenotype of mammary epithelial cells in 3-dimensional culture, inhibited oncogene-mediated breast tumorigenesis, blocked breast cancer epithelial cell DNA synthesis, colony formation, growth in matrigel, inhibited epithelial mesenchymal transition (EMT), tumor growth and metastasis in mice. Genetic deletion of Dach1 in the mouse results in perinatal lethality therefore we developed conditional Dach1 knockout tri- transgenic systems. Our studies provide support for a model in which DACH1 physical interactions with specific proteins coordinate DACH1-tumor suppression. These interactions govern growth suppression in breast tumor genetic subtype specific manner. DACH1 binds p53 to enhance p53 tumor suppressor functions. DACH1 binds and inhibits the function of growth inducing proteins through distinct mechanisms (YB-1, EYA1, FKHR) (Fig. 1). These studies will further characterize a novel tumor and metastasis suppressor pathway. We hypothesize that inactivation of the DACH1/EYA pathway is a key signaling event contributing to mammary tumorigenesis and metastasis. We will determine the mechanism by which DACH1 inhibits breast tumor cellular proliferation and metastasis in vivo. Photo-uncaging to induce single cell level Cre excision will allow determination of sister cell interactions and the in vivo significance of a new model of tumor suppression. Functional analyses of DACH1-secreted factors and synthetic lethal screens will identify new cancer targets.
Breast cancer is the second commonest cause of cancer death in women in the United States, and therapy resistance is driven in part by the expansion of breast tumor stem cells (BTSC). We have shown that Dach1, a component of the Retinal Determination Gene Network (RDGN), inhibits governs breast cancer tumor growth and BTSC. These studies aim to identify breast cancer secreted factors and small molecule inhibitors which govern breast cancer stem cell expansion to form the basis of a novel approach to breast cancer treatment.
|Wu, Kongming; Chen, Ke; Wang, Chenguang et al. (2014) Cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation. Cancer Res 74:829-39|
|Yu, Zuoren; Xu, Zengguang; Disante, Gabriele et al. (2014) miR-17/20 sensitization of breast cancer cells to chemotherapy-induced apoptosis requires Akt1. Oncotarget 5:1083-90|
|Velasco-Velázquez, Marco; Xolalpa, Wendy; Pestell, Richard G (2014) The potential to target CCL5/CCR5 in breast cancer. Expert Opin Ther Targets 18:1265-75|
|Sicoli, Daniela; Jiao, Xuanmao; Ju, Xiaoming et al. (2014) CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines. Cancer Res 74:7103-14|
|Casimiro, Mathew C; Velasco-Velázquez, Marco; Aguirre-Alvarado, Charmina et al. (2014) Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opin Investig Drugs 23:295-304|
|Wu, Kongming; Li, Zhaoming; Cai, Shaoxin et al. (2013) EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1. Cancer Res 73:4488-99|
|Velasco-Velazquez, Marco A; Homsi, Nora; De La Fuente, Marisol et al. (2012) Breast cancer stem cells. Int J Biochem Cell Biol 44:573-7|
|Yu, Zuoren; Pestell, Richard G (2012) Small non-coding RNAs govern mammary gland tumorigenesis. J Mammary Gland Biol Neoplasia 17:59-64|
|Katiyar, Sanjay; Jiao, Xuanmao; Addya, Sankar et al. (2012) Mammary gland selective excision of c-jun identifies its role in mRNA splicing. Cancer Res 72:1023-34|
|Velasco-Velazquez, Marco A; Li, Zhiping; Casimiro, Mathew et al. (2011) Examining the role of cyclin D1 in breast cancer. Future Oncol 7:753-65|
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