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  • The EMBO Journal (2004) 23, 3397 - 3407
  • doi:10.1038/sj.emboj.7600323

Published online: 15 July 2004

Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis

Gerburg Wulf1, Priti Garg1, Yih-Cherng Liou1,a, Dirk Iglehart2 and Kun Ping Lu1

  1. Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  2. Department of Surgery, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, USA

Correspondence to:

Kun Ping Lu, Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, HIM 1047, Boston, MA 02215, USA. Tel.: +1 617 667 4143; Fax: +1 617 667 0610; E-mail: klu@bidmc.harvard.edu

aPresent address: Departments of Biochemistry and Biological Sciences, National University of Singapore, 117597, Singapore

Received 24 February 2004; Accepted 21 June 2004

Phosphorylation on certain Ser/Thr-Pro motifs is a major oncogenic mechanism. The conformation and function of phosphorylated Ser/Thr-Pro motifs are further regulated by the prolyl isomerase Pin1. Pin1 is prevalently overexpressed in human cancers and implicated in oncogenesis. However, the role of Pin1 in oncogenesis in vivo is not known. We have shown that Pin1 ablation is highly effective in preventing oncogenic Neu or Ras from inducing cyclin D1 and breast cancer in mice, although it neither affects transgene expression nor mammary gland development. Moreover, we have developed an ex vivo assay to uncover that a significant fraction of primary mammary epithelial cells from Neu or Ras mice display various malignant properties long before they develop tumors in vivo. Importantly, these early transformed properties are effectively suppressed by Pin1 deletion, which can be fully rescued by overexpression of cyclin D1. Thus, Pin1 is essential for tumorigenesis and is an attractive anticancer target. Our ex vivo assay can be used to study early events of breast cancer development in genetically predisposed mice.

  • Keywords:

    • Pin1,
    • protein phosphorylation,
    • three-dimensional culture,
    • transgenic mice,
    • tumorigenesis