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.
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.
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|Xu, Yan; Xu, Yixiang; Liao, Lan et al. (2013) Inducible knockout of Twist1 in young and adult mice prolongs hair growth cycle and has mild effects on general health, supporting Twist1 as a preferential cancer target. Am J Pathol 183:1281-92|
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