Combined PTEN and p27kip1 Protein Expression Patterns Are Associated with Obesity and Prognosis in Endometrial Carcinomas

Abstract

Purpose: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) and p27 kip1 proteins are key players of the Akt pathway, which is nutritionally regulated by insulin receptor signaling and influenced by estrogens. In this study, the prognostic relevance of the PTEN/ p27 kip1 protein expression in endometrial carcinoma in relationship to the body mass index (BMI) was determined. Endometrial cancer represents a major health problem. During the first half of the 20th century, the incidence of cervical cancer was greater than the cancer of the endometrium by a ratio of >3:1, but this trend reversed during the last 50 years (1). Today, endometrial carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in women after carcinomas of the breast, colon, and lung in the western world (2). Epidemiologic data provide a strong link between excess body weight and the risk of developing endometrial carcinoma (3 -6).Endometrial carcinomas are subdivided into two major types based on epidemiology, histopathology, and clinical behavior. Type I tumors are endometrioid endometrial carcinomas (EEC) and type II tumors are non-EEC (NEEC). Type I tumors occur predominantly in perimenopausal women under unopposed estrogenic stimulation. These tumors are frequently preceded by atypical endometrial hyperplasia. They are usually low-grade and confined to the uterus, and most women are cured due to an early detection following the initial symptom of irregular uterine bleeding. In contrast, type II tumors develop mainly in elder women in whom the endometrium is atrophic due to the absence of an estrogenic effect. These tumors are predominantly high-grade serous or clear-cell carcinomas. NEEC invade early into the myometrium. They are aggressive and associated with a less favorable clinical outcome. Whereas EEC are due to increased estrogen hormone levels, mainly in obese, younger patients, NEEC are observed in older patients without increased estrogen levels and without an association with obesity.

Pathologic Scoring of PTEN Immunohistochemistry in Endometrial Carcinoma is Highly Reproducible

“…It also appears that PTEN immunohistochemistry performs equally well in both histologic subtypes of endometrial carcinoma, as there was no difference in kappa for endometrioid versus non-endometrioid carcinomas. Similar to prior studies, we noted loss of PTEN staining more frequently in endometrioid compared to non-endometrioid tumors (8, 9, 10, 12, 28). …”

Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity

“…In normal weight women, p27 expression levels are lowest in follicular endometrium and highest in luteal phase endometrium as assessed by endometrial biopsies and western analysis, with p27 levels inversely correlated with activation of mitogenic PI3K/mTORC1 signaling (phosphorylation of S6 ribosomal protein) ((37, 38) and Supplemental Figure S1). …”

PTEN deletion is rare but often homogeneous in gastric cancer

“…Studies using FISH for PTEN deletion detection demonstrated the presence of PTEN genomic losses and its impact on development of advanced disease, for example in prostate cancer,37 gliomas38 and endometrial cancer 39…”