Transforming Growth Factor-β, Estrogen, and Progesterone Converge on the Regulation of p27Kip1 in the Normal and Malignant Endometrium

Hormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-β (TGF-β) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-β–mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 (p27) to arrest cells in G1 phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-β induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-β, 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-β induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-β cannot induce p27 levels due to dysregulated TGF-β signaling, thereby causing 17β-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]