P53/MDM2 overexpression in metastatic endometrial cancer: correlation with clinicopathological features and patient outcome

Abstract

Several studies have reported that p53/mdm2 distortions play a pivotal role in the development and progression of various human malignancies. However, the number of reports having evaluated simultaneously the components of the P53-pathway alterations in advanced-stage human endometrial carcinomas (EC) is low. In this study, we examined the expression of P53/MDM2 proteins in primary and metastatic ECs, and analyzed the clinicopathological characteristics as well as the survival outcome of patients in relation to P53/MDM2 overexpression. The study group comprised 36 patients with advanced EC, whose primary and metastatic tumor slides were sufficient for analysis. Immunohistochemical assessment was made by applying anti-human P53 and MDM2 antibodies and a highly sensitive EnVision(+)/HPR visualization system. Nuclear P53 overexpression was seen in 11 (31%) primary ECs and 12 (33%) metastatic tumors. There was a significant correlation between P53 overexpression (in primary cancers and metastatic tumors) and MDM2 overexpression in metastatic tumors. Nuclear MDM2 overexpression was noted in 42% (15/36) of primary carcinomas and in 47% (17/36) of metastatic tumors. A significant association existed between MDM2 overexpression and histological grading (G1 + G2 versus G3, P = 0.043). P53/MDM2 overexpression occurred simultaneously in 7 out of 36 (19%) primary ECs and in 9 out of 36 (25%) metastatic lesions. Concomitant overexpression of these proteins was reported in 7 out of 36 (19%) cases and tended to be higher in tumors showing VSI compared to neoplasms lacking vascular space invasion (P = 0.051). P53 overexpression, either in primary ECs (P < 0.0001) or metastatic lesions (P < 0.0001), was significantly associated with poor survival in univariate analysis. Moreover, the log-rank test demonstrated that simultaneous P53/MDM2 overexpression was also correlated with decreased length of survival. There was no correlation between MDM2 overexpression and patient survival. Multivariate Cox regression analysis revealed that only P53 overexpression is an independent predictor of survival. In conclusion, our data support the view that patients with P53 overexpression are significantly associated with an unfavorable outcome, whereas MDM2 overexpression is not related to decreased survival length in women operated on for advanced-stage EC.

Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin

“…Several studies have shown that amplification of the mdm2 gene occurs more frequently in metastatic and recurrent cancers than in primary tumors (39). Overexpression of mdm2 was detected in metastatic endometrial tumors (40). It was reported recently that mdm2 promotes cell motility and invasiveness by regulating E-cadherin degradation (11).…”

Role of p53 Pathway Alterations in Uterine Carcinosarcomas (Malignant Mixed Müllerian Tumors)

“…The mutant of the altered p53 oncoprotein has a prolonged cellular half-life and is accumulated to detectable levels by various techniques, including Western blotting and immunohistochemistry [63,66,67]. TP53 alterations have been detected in different human neoplasms and cell lines, and protein overexpression is associated with an unfavorable patient outcome [68,69,70], particularly in females with advanced-stage ECs [71,72]. p53 overexpression was detected more frequently in nonendometrioid than in endometrioid tumor types originating from different sites, and more often in grade 3 tumors than in grade 1 and 2 neoplasms [1,2,72,73,74,75].…”

Does high-grade endometrioid carcinoma (grade 3 FIGO) belong to type I or type II endometrial cancer? A clinical–pathological and immunohistochemical study

“…For p53, the percentage of cells with positive nuclear staining in a minimum of 500 histologically identified neoplastic cells was recorded, and staining patterns were subsequently calculated according to the scale previously published by Alkushi et al [11] and Jeczen et al [12]: 0, less than 10% of tumor cells expressed p53; 1, 10-50% of cancer cells expressed p53; and 2, more than 50% of the tumor cells expressed p53. A staining score of 2 was considered to indicate overexpression of the protein.…”