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 (eclipse). The RDGN genetic network, consisting of the dachshund (dac), eyes absent (eya), eyeless, and sine oculis (so) genes, regulates cell fate determination in metazoans. Our analysis of over 2,000 patients demonstrated increased nuclear DACH1 expression correlated inversely with cellular mitosis and predicted a ~40 month improved breast cancer patient survival. We have shown DACH1 inhibits oncogene-mediated breast oncogenesis, blocking breast cancer epithelial cell DNA synthesis, colony formation, growth in matrigel and tumor growth in mice. Genetic deletion of DACH1 in the mouse results in perinatal lethality. To determine the molecular mechanisms by which DACH1 inhibits mammary tumorigenesis and to determine to functional significance of DACH1 in vivo we will:
Aim 1. Determine the mechanisms governing DACH1/Eya inhibition of breast tumor cellular proliferation. We will determine the DACH1 binding proteins governing breast tumor growth we will characterize these components in human breast cancer and investigate allelic inactivation of DACH1. We will define endogenous gene targets of DACH1 using ChIP on chip assays.
Aim 2. Determine the role of DACH1 as a suppressor of mammary tumor onset, progression and metastasis using Dach1f1/f1 transgenic mice. The role of DACH1 as a suppressor of mammary tumorigenesis will be analyzed using DACH1 shRNA and Dach1fl/fl transgenic mice in primary culture and transgenic mice (MMTV-Cre/MMTV-ErbB2).
Aim 3. Determine the mechanism by which DACH1/Eya inhibits cellular migration. DACH1 inhibits cellular migration and chemotaxis. Using a proteomic approach DACH1 was shown to regulate expression and production of secreted cytokines from breast cancer cells. We will characterize the contribution of these factors to breast cancer metastasis in vivo in using heterotypic breast cancer transplant models. These studies will characterize a completely novel tumor and metastasis suppressor pathway. We will determine the mechanism by which DACH1 inhibits breast tumor cellular proliferation and metastasis in vivo.

Public Health Relevance

This year in the United States 41,000 will die from breast cancer resistant to the current forms of therapy. In order for us to find new approaches to treatment of breast cancer new models of breast cancer progression and new molecular targets are required. We have identified a completely novel pathway of genes that block breast cancer growth and spread that when lost in human breast cancer, predict very bad outcome. We and will determine how this new gene pathway blocks breast cancer cellular growth and metastasis to provide the basis for new types of therapies for breast cancer

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132115-04
Application #
8291884
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2009-07-20
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$310,970
Indirect Cost
$109,695
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Zhao, Qian; Deng, Shengqiong; Wang, Guangxue et al. (2016) A direct quantification method for measuring plasma MicroRNAs identified potential biomarkers for detecting metastatic breast cancer. Oncotarget 7:21865-74
Ozcan, Lale; Ghorpade, Devram S; Zheng, Ze et al. (2016) Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep 15:2214-25
Casimiro, Mathew C; Di Sante, Gabriele; Ju, Xiaoming et al. (2016) Cyclin D1 Promotes Androgen-Dependent DNA Damage Repair in Prostate Cancer Cells. Cancer Res 76:329-38
Wu, Kongming; Yuan, Xun; Pestell, Richard (2015) Endogenous Dach1 in cancer. Oncoscience 2:803-4
Xu, Hanxiao; Tian, Yijun; Yuan, Xun et al. (2015) The role of CD44 in epithelial-mesenchymal transition and cancer development. Onco Targets Ther 8:3783-92
Sun, X; Jiao, X; Pestell, T G et al. (2014) MicroRNAs and cancer stem cells: the sword and the shield. Oncogene 33:4967-77
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
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
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
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

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