Strongly reduced expression of the cell cycle inhibitor p27 in endometrial neoplasia

Abstract

In the present study we investigated the expression of the cell cycle inhibitor p27 in endometrial neoplasia using immunohistochemistry with a p27-specific antibody. Expression of p27 in endometrial carcinomas was compared with expression in the normal endometrium throughout the cycle. Normal endometrial cells showed strong nuclear expression of p27. Expression was present throughout the cycle and was stronger during the secretory phase. We found strongly reduced or abolished expression of p27 in endometrial carcinoma (85.3% of cases). The 41 tumours analysed were classified according to p27 staining intensity and percentage of positive cells into the following categories of p27 expression: negative/very low (56.0%); low (29.3%); moderate (14.7%) and high (0.0%). All the p27-positive tumours were well-differentiated endometrioid carcinomas of malignancy grade G1. Comparison with the p53 status showed that all tumours with strong p53 expression had low/negative p27 staining, while those that were positive for p27 had negative/low p53 staining. Reduced or absent p27 levels were also observed by Western blot analysis both in tumour samples and in HEC-1B endometrial adenocarcinoma cells. It thus seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis.

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

“…The fact that MT-hGHRH transgenic mice with intact p27 were hyperprolactinemic and had elevated GH and IGF-I levels but normal uterine histologic features suggest that p27 protects endometrial cells from growth factor stimulation (prolactin, IGF-I and/or estrogen). This hypothesis is consistent with the fact that the p27 protein is not detectable in hyperplastic and neoplastic endometrial tissue (Bamberger et al, 1999b) but can be induced by medroxyprogesterone acetate, a treatment that also suppresses endometrial cell proliferation (Shiozawa et al, 1998).…”

Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells

“…Second, Skp2, the oncogenic subunit of the Skp1/Cul1/F-box protein complex that directs FOXO1 ubiquitination and proteasomal degradation, is overexpressed in EECs (Lahav-Baratz et al, 2004). Third, the expression of known FOXO target genes, such as the cyclin-dependent kinase inhibitor p27 kip , is dramatically lower in malignant endometrium (Bamberger et al, 1999). Moreover, unopposed oestrogen signalling, a well-recognized risk factor for EEC (Amant et al, 2005;Shang, 2006), has been shown to enhance PI3K/Akt activity through binding of oestrogen receptor a (ERa) to the p85a regulatory subunit of PI3K .…”

Paradoxical expression of cell cycle inhibitor p27 in endometrioid adenocarcinoma of the uterine corpus – correlation with proliferation and clinicopathological parameters

“…In the endometrium, it was reported that p27 was expressed in the secretory phase, but less in the proliferative phase (Shiozawa et al, 1998;Bamberger et al, 1999). Its expression was also higher in endometrial hyperplasia than in the proliferative phase and was significantly increased when the former was treated with medroxyprogesterone acetate (Shiozawa et al, 1998).…”