My long-term goal is to understand 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-10b induced tumor invasion and distant metastasis in two orthotopic models of breast cancer. In the K99 phase of this award, I discovered that therapeutic silencing of miR-10b 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 R00 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 miR-10b In normal development and In metastatic progression of spontaneous breast cancer;and I will explore the cell non-autonomous effects of miR-10b In metastasis formation. In parallel, I will perform pre-clinical studies with the miR-9 antagomir;and I will also investigate E-cadherin-independent functions of miR-9 in tumor cells. Taken together, these studies will enable more precise evaluation 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.
(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.
|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|
|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, Peijing; Wang, Li; Rodriguez-Aguayo, Cristian et al. (2014) miR-205 acts as a tumour radiosensitizer by targeting ZEB1 and Ubc13. Nat Commun 5:5671|
|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|
|Sun, Yutong; Zhang, Jinsong; Ma, Li (2014) ?-catenin. A tumor suppressor beyond adherens junctions. Cell Cycle 13:2334-9|
|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, Jinsong; Zhang, Peijing; Wei, Yongkun et al. (2013) Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol 15:1486-1494|
|Chen, Dahu; Sun, Yutong; Wei, Yongkun et al. (2012) LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat Med 18:1511-7|
|Piao, Hai-Long; Ma, Li (2012) Non-coding RNAs as regulators of mammary development and breast cancer. J Mammary Gland Biol Neoplasia 17:33-42|
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