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Transforming Growth Factor-ß, Estrogen, and Progesterone Converge on the Regulation of p27^Kip1 in the Normal and Malignant Endometrium

Departments of Pathology and Medicine, New York University Cancer Institute, New York University School of Medicine, New York, New York

Requests for reprints: Leslie I. Gold, New York University School of Medicine, 550 First Avenue, NB16S13, New York, NY 10016. Phone: 212-263-6320; Fax: 212-263-7640; E-mail: Leslie.gold{at}med.nyu.edu.

Hormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-ß (TGF-ß) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-ß–mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27^Kip1 (p27) to arrest cells in G₁ phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-ß induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-ß, which was 2-fold higher in the nuclear fraction; mRNA levels were unaffected. In addition, ECA tissue lysates show a high rate of ubiquitin-mediated degradation of p27 compared with normal secretory-phase endometrial tissue (SE) such that 4% and 89% of recombinant p27 added to the lysates remains after 3 and 20 h, respectively. These results are reflected in vivo as ECA tissue lacks p27 compared with high expression of p27 in SE (P 0.001). Furthermore, we show that estrogen treatment of EECs causes mitogen-activated protein kinase–driven proteasomal degradation of p27 whereas progesterone induces a marked increase in p27 in both normal EECs and ECA cells. Therefore, these data suggest that TGF-ß induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-ß cannot induce p27 levels due to dysregulated TGF-ß signaling, thereby causing 17ß-estradiol–driven p27 degradation to proceed unchecked for cell cycle progression. Thus, p27 may be a central target for growth regulation of normal endometrium and in the pathogenesis of ECA. [Cancer Res 2007;67(3):1007–18]

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