These studies aim to define at a higher level of resolution the mechanism by which 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132115-09
Application #
9221991
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Snyderwine, Elizabeth G
Project Start
2007-12-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baruch S. Blumberg Institute
Department
Type
DUNS #
167281851
City
Doylestown
State
PA
Country
United States
Zip Code
18902
Casimiro, Mathew C; Di Sante, Gabriele; Di Rocco, Agnese et al. (2017) Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis. Cancer Res 77:3391-3405
Pestell, Timothy G; Jiao, Xuanmao; Kumar, Mukesh et al. (2017) Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth. Oncotarget 8:81754-81775
Di Sante, Gabriele; Di Rocco, Agnese; Pupo, Claudia et al. (2017) Hormone-induced DNA damage response and repair mediated by cyclin D1 in breast and prostate cancer. Oncotarget 8:81803-81812
Xu, Hanxiao; Yu, Shengnan; Yuan, Xun et al. (2017) DACH1 suppresses breast cancer as a negative regulator of CD44. Sci Rep 7:4361
Xu, Hanxiao; Yu, Shengnan; Liu, Qian et al. (2017) Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol 10:97
Kong, Deguang; Liu, Yu; Liu, Qian et al. (2016) The retinal determination gene network: from developmental regulator to cancer therapeutic target. Oncotarget 7:50755-50765
Ju, Xiaoming; Jiao, Xuanmao; Ertel, Adam et al. (2016) v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1. Cancer Res 76:6723-6734
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 15:2214-2225
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
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

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