Metastasis (Meta) is responsible for almost all breast cancer (BC) mortality;however, its pathophysiological mechanism is poorly understood. The long-term goal of this project is to understand the molecular mechanisms of BC Meta and develop new ideas/strategies to control BC Meta. The steroid receptor coactivator 1 (SRC-1) is a newly identified Meta gene and it promotes Twist expression to enhance BC cell epithelial-mesenchymal transition (EMT) and lung Meta. Twist is a DNA-binding transcription factor overexpressed in invasive BCs and a master regulator of EMT and BC Meta. Twist expression in BC is also associated with acquisition of chemotherapy resistance. In addition, the BC cell plasticity between EMT and mesenchymal epithelial transition (MET) has been proposed to be convertible and play a crucial role in Meta, but direct in vivo evidences for such sequential events and their direct link to Meta are still absent. In the current project, the investigators hypothesize that BC cell EMT-MET plasticity exists in both local and metastatic tumors. Twist plays a role in promoting EMT and suppressing MET. Inactivation of Twist will enhance the efficacy of BC chemotherapy without causing severe health problems in adults. Twist protein stability is controlled by phosphorylation, and inhibition of kinase responsible for such phosphorylation combined with an increase in corresponding phosphotase activity will reduce Twist protein level and its function in BC cells.
Three specific aims (SAs) are proposed to test these hypotheses. The first SA is to define the role of Twist in MG tumor cell plasticity and the role of MG tumor cell plasticity in BC Meta. An EMT- dependent promoter-reporter senor system will be used to trace the EMT cell lineage during the processes of BC cell EMT-MET plasticity and lung Meta. Lentivirus will be used to induce mouse mammary tumors with endogenous expression, overexpression or knockout (KO) of Twist to determine the role of Twist in tumor cell plasticity and Meta. The second SA is to evaluate the side effects of Twist inactivation on general health and test whether targeting Twist enhances BC chemotherapy efficacy. Twist will be knocked out in adult mice using an inducible KO system. Investigators will examine whether Twist KO in adult mice causes any severe health problems and whether Twist KO will enhance the efficacy of Paclitaxel chemotherapy. This will provide information about whether Twist can be used as a cancer therapy target with tolerable side effects. With the inducible KO model, the effect of Twist inactivation on BC chemotherapy will be determined. The third SA is to define the role and molecular mechanisms of Twist phosphorylation in regulation of its protein stability and test whether destabilization of Twist by controlling its phosphorylation degree will inhibit BC cel invasion and Meta. Successful results from these studies will not only provide insights into understanding how Twist regulates BC cell plasticity and cancer Meta, but also validate Twist as a target for controlling BC Meta and provide direct in vivo evidence to prove or disprove the sequential connection between EMT and MET during BC Meta.

Public Health Relevance

Metastasis is the major cause of death in breast cancer as well as other cancers. Twist is a DNA-binding protein that promotes metastasis by altering gene expression. This project will define the in vivo role of Twist in breast cancer cell phenotypic changes and metastasis, evaluate the target value and side effects of Twist inactivation in animal cancer therapy, test possible synergistic effects of combined Twist inactivation and chemotherapy on breast cancer metastasis in mouse models, and investigate new strategies to reduce Twist protein level and function in breast cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA112403-06A1
Application #
8295580
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2004-12-01
Project End
2017-03-31
Budget Start
2012-04-09
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$269,732
Indirect Cost
$97,379
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Rohira, Aarti D; Yan, Fei; Wang, Lei et al. (2017) Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells. Cancer Res 77:4293-4304
Chen, Wenbo; Lu, Xuqiang; Chen, Yuan et al. (2017) Steroid Receptor Coactivator 3 Contributes to Host Defense against Enteric Bacteria by Recruiting Neutrophils via Upregulation of CXCL2 Expression. J Immunol 198:1606-1615
Xu, Yixiang; Lee, Dong-Kee; Feng, Zhen et al. (2017) Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice. Proc Natl Acad Sci U S A 114:11494-11499
Xu, Y; Qin, L; Sun, T et al. (2017) Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression. Oncogene 36:1157-1166
Xi, Ying; Kim, Thomas; Brumwell, Alexis N et al. (2017) Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol 19:904-914
Wang, Ziqing; Zhang, Feng; He, Jingquan et al. (2017) Binding of PLD2-Generated Phosphatidic Acid to KIF5B Promotes MT1-MMP Surface Trafficking and Lung Metastasis of Mouse Breast Cancer Cells. Dev Cell 43:186-197.e7
Wu, Hongmei; Bi, Jiong; Peng, Yan et al. (2017) Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer. Oncotarget 8:54364-54377
Qin, Li; Xu, Yixiang; Yu, Xiaobin et al. (2017) The histone demethylase Kdm3a is required for normal epithelial proliferation, ductal elongation and tumor growth in the mouse mammary gland. Oncotarget 8:84761-84775
Sreekumar, Amulya; Toneff, Michael J; Toh, Eajer et al. (2017) WNT-Mediated Regulation of FOXO1 Constitutes a Critical Axis Maintaining Pubertal Mammary Stem Cell Homeostasis. Dev Cell 43:436-448.e6
Sun, Tong; Fu, Junjiang; Shen, Tao et al. (2016) The Small C-terminal Domain Phosphatase 1 Inhibits Cancer Cell Migration and Invasion by Dephosphorylating Ser(P)68-Twist1 to Accelerate Twist1 Protein Degradation. J Biol Chem 291:11518-28

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