DF/HCC Program Affiliation

Member, Breast Cancer Program

Research Abstract

Much cancer research focuses on the molecular mechanisms of neoplastic transformation with the hope that understanding the mechanisms of carcinogenesis will provide keys to the development of new therapeutic avenues. A major therapeutic target is the cell cycle machinery of cancer cells. My work in the last several years has focused on the mechanisms that link cell cycle control with oncogenesis, specifically on the role of the prolyl isomerase Pin1 in breast cancer. Pin1 regulates the function of a subset of phosphoproteins, presumably by binding and isomerizing their phosphorylated S/T-P motifs. Inhibition of Pin1 causes growth arrest in tumor cells and contributes to neuronal death in Alzheimer's disease. We found that Pin1 is overexpressed in human breast cancer cell lines and 75% of breast cancer tissues, and that its levels correlate with the nuclear grade of the tumors and their cyclin D1 protein and mRNA expression. Pin1 mRNA levels were elevated in those tumors examined suggesting that Pin1 expression is at least in part regulated on the transcriptional level. Induced expression of Pin1 elevates cellular cyclin D1 levels and activates its promoter through the AP-1 site. Importantly, Pin1 binds to phosphorylated c-Jun and dramatically increases its ability to activate the cyclin D1 promoter in cooperation either with oncogenic Ha-Ras or activated JNK; these effects depend on phosphorylation of c-Jun on S63/73-P and the isomerase activity of Pin1. Given the crucial roles of Ras signaling and cyclin D1 overexpression in oncogenesis, my results suggest that overexpression of Pin1 may promote tumor growth. To examine this hypothesis, I am currently analyzing the significance of Pin1 for mammary tumorigenesis in a mouse model.

Publications

• Lu KP, Suizu F, Zhou XZ, Finn G, Lam P, Wulf G. Targeting carcinogenesis: a role for the prolyl isomerase Pin1? Mol Carcinog 2006 Jun; 45(6):397-402
  PMID: 16652378
• Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 2006 Mar 23; 440(7083):528-34
  PMID: 16554819