My long-term goal is to uniJerstanid the role and mechanisms of microRNAs In regulating tumor metastasis, and to develop new candidate therapies for malignant diseases. It has become increasingly evident that cancer pathogenesis can Involve a superfamily of small non-coding RNAs named microRNAs. While the oncogenic or tumor-suppressing functions of a number of microRNAs have been characterized, the role played by microRNAs in mediating metastasis was addressed only recently by work from myself and several other groups. In my initial screening, I Identified three microRNAs that are most significantly upregulated in human breast cancer cell lines: mlR-155, miR-9, and miR-10b. Subsequent funcitonal experiments demonstrated that overexpression of miR-IOb induced tumor invasion and distant metastasis in two orthotopic models of breast cancer. In the K99 phase of this award, I discovered that therapeutic silendng of miR-1 Ob with 'antagomirs'suppressed metastasis in a mouse mammary tumor model. In addition, I Identified miR-9 as an E-cadherin-suppressIng and metastasis-promoting microRNA. In the ROO phase, I will extend these previous-studies by using molecular, genetic, pharmacological, and genomic approaches. Specifically, I will pursue the antagomlr-10b study by using multiple models and testing combination therapies In mice;I will establish a genetically engineered mouse model to determine the role and mechanisms of mtR-10b In normal development and In metastatic progression of spontaneous breast cancer;and I will explore the cell non-autonomous effects of mlR-lOb In metastasis formation. In parallel, I will perform pre-cllnical studies with the miR-9 antagomir;and I will also investigate E-cadherln-independent functions of miR-9 in tumor cells. Taken together, these studies will enable rnore precise eveluation of the role and mechanisms of these microRNAs In malignant progression, and will allow me to launch my independent research program and obtain preliminary data for R01 application.

Public Health Relevance

(See Inslruclions): 90% of cancer-related mortality is caused by metastasis. Current cancer treatments can control many primary tumors but do little to stop the metastatic spread. Not only does this study Illuminate the genetic and molecular basis of tumor metastasis, but it also has Implications for breast cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA138572-05
Application #
8323981
Study Section
Special Emphasis Panel (NSS)
Program Officer
Jhappan, Chamelli
Project Start
2010-09-24
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$241,475
Indirect Cost
$88,643
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Chen, Dahu; Sun, Yutong; Yuan, Yuan et al. (2014) miR-100 induces epithelial-mesenchymal transition but suppresses tumorigenesis, migration and invasion. PLoS Genet 10:e1004177
Zhang, Peijing; Wei, Yongkun; Wang, Li et al. (2014) ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat Cell Biol 16:864-75
Zhang, Jinsong; Zhang, Peijing; Wang, Li et al. (2014) Long non-coding RNA HOTAIR in carcinogenesis and metastasis. Acta Biochim Biophys Sin (Shanghai) 46:1-5
Piao, Hai-Long; Yuan, Yuan; Wang, Min et al. (2014) ?-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-?B signalling. Nat Cell Biol 16:245-54
Ma, Li (2014) Determinants of breast cancer progression. Sci Transl Med 6:243fs25
Zhang, Jinsong; Zhang, Peijing; Wei, Yongkun et al. (2013) Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol 15:1486-94