Pin1 regulates the function of a subset of phosphoproteins, presumably by binding and isomerizing their phosphorylated S/T-P motifs (11-20). Inhibition of Pin1 causes growth arrest of tumor cells and contributes to neuronal death in Alzheimer's disease (11). I found that Pin1 is overexpressed in 75% of breast cancer specimens, and that it cooperates with Ras signaling in increasing c-Jun's transcriptional activity towards cyclin D1 (12). Pin1 also causes cyclin D1 accumulation by regulating the turnover and subcellular localization of beta-catenin (81). Loss of Pin1 function in knock-out mice mimics the cyclin D1 null phenotype and causes severe defects in mammary gland development (84). Given the crucial roles of Ras signaling and cyclin D1 in oncogenesis, our results suggest that overexpression of Pin1 may promote breast cancer growth. This proposal is to test this hypothesis with the following specific aims: (1) To examine the mechanism of overexpression of Pin1 in breast cancer a. examine whether overexpression of Pin1 is due to amplification or mutation. b. examine the transcriptional regulation of the Pin1 promoter. (2) To study the role of Pin1 in the transcription of specific genes a. define the role of Pin1 phosphorylation in its interaction with c-Jun b. analyze how Pin1 regulates c-jun stability and function. c. establish a profile of the genes that are specifically activated by Pin1. (3) To study the role of Pin1 in the development of cancer in vitro and in vivo a. analyze the transforming activity of Pin1 itself or in cooperation with Ras or ErbB2. b. analyze the significance of Pin1 for breast cancer development in a mouse model. (4) To study the effect of the inhibition of Pin1's PPIase activity as potential cancer therapy in vitro and in vivo. This project is designed to train the principal investigator for a career as an independent physician scientist.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Subcommittee G - Education (NCI)
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Lohrey, Nancy
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Beth Israel Deaconess Medical Center
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Burga, Laura N; Hu, Hai; Juvekar, Ashish et al. (2011) Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptor-negative cancers in BRCA1-mutant mice. Breast Cancer Res 13:R30
Burga, Laura N; Tung, Nadine M; Troyan, Susan L et al. (2009) Altered proliferation and differentiation properties of primary mammary epithelial cells from BRCA1 mutation carriers. Cancer Res 69:1273-8
Lam, Prudence B; Burga, Laura N; Wu, Bryan P et al. (2008) Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability. Mol Cancer 7:91
Chen, Shao-Yong; Wulf, Gerburg; Zhou, Xiao Zhen et al. (2006) Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction. Mol Cell Biol 26:929-39
Lu, Kun Ping; Suizu, Futoshi; Zhou, Xiao Zhen et al. (2006) Targeting carcinogenesis: a role for the prolyl isomerase Pin1? Mol Carcinog 45:397-402
Wulf, Gerburg; Finn, Greg; Suizu, Futoshi et al. (2005) Phosphorylation-specific prolyl isomerization: is there an underlying theme? Nat Cell Biol 7:435-41
Wulf, Gerburg; Garg, Priti; Liou, Yih-Cherng et al. (2004) Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J 23:3397-407
Wulf, Gerburg; Ryo, Akihide; Liou, Yih-Cherng et al. (2003) The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Res 5:76-82
Ryo, Akihide; Suizu, Futoshi; Yoshida, Yasuhiro et al. (2003) Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 12:1413-26
Ryo, Akihide; Liou, Yih-Cherng; Lu, Kun Ping et al. (2003) Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer. J Cell Sci 116:773-83

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