The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy.

Mitsuhiro Nakamura,Takiko Daikoku,Hiroshi Fujiwara,Takeshi Obata

doi:10.3390/ijms20215482

Abstract

Dysfunction of p53 is observed in the many malignant tumors. In cervical cancer, p53 is inactivated by degradation through the complex with human papilloma virus (HPV) oncoprotein E6 and E6-associated protein (E6AP), an E3 ubiquitin protein ligase. In endometrial cancer, overexpression of p53 in immunohistochemistry is a significant prognostic factor. A discrepancy between p53 overexpression and TP53 mutations is observed in endometrioid endometrial cancer, indicating that the accumulation of p53 protein can be explained by not only gene mutations but also dysregulation of the factors such as ERβ and MDM2. Furthermore, the double-positive expression of immunoreactive estrogen receptor (ER) β and p53 proteins is closely associated with the incidence of metastasis and/or recurrence. High-grade serous ovarian carcinoma (HGSC) arises from secretary cells in the fallopian tube. The secretary cell outgrowth (SCOUT) with TP53 mutations progresses to HGSC via the p53 signature, serous intraepithelial lesion (STIL), and serous intraepithelial carcinoma (STIC), indicating that TP53 mutation is associated with carcinogenesis of HGSC. Clinical application targeting p53 has been approved for some malignant tumors. Gene therapy by the adenovirus-mediated p53 gene transfer system is performed for head and neck cancer. A clinical phase III trial using MDM2/X inhibitors, idasanutlin (RG7388) combined with cytarabine, is being performed involving relapse/refractory acute myeloid leukemia patients. The use of adenoviruses as live vectors which encode wild-type p53 has given promising results in cervical cancer patients.

Highlights

In 1979, p53 protein was first discovered as a 53-k Dalton protein from SV40 transformed cells [1]
All 5 cases analyzed showed the same TP53 mutations between serous intraepithelial carcinoma (STIC) and carcinomas [91]. These findings indicate that STIC may be a precursor lesion of pelvic serous carcinoma, including tubal, ovarian, and peritoneal carcinomas, and the carcinogenesis of these carcinomas might be associated with TP53 mutations
The dysfunction of p53 is associated with carcinogenesis in cervical and ovarian cancers

Summary

Introduction

In 1979, p53 protein was first discovered as a 53-k Dalton protein from SV40 transformed cells [1]. P53 protein activated by several signals, such as DNA damage, hypoxia, oncogene expression, ribonucleotide depletion, and osmotic stress, acts mainly as a transcriptional factor. If the cells cannot repair the DNA damage, p53 induces apoptosis by activating apoptosis signal genes, such as BAX, PUMA, Noxa, and PERP [6]. Dysfunction of p53 in malignant tumors is mainly due to the inactivation of p53 protein by binding proteins or TP53 mutations. Mdm protein acts both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation. In gynecologic cancer cell lines, HPV-negative cervical cancer cell line, C33A has missense mutation, c.817C > T in exon8 [15]. We introduce the significance of p53 and potential clinical applications using p53 in these malignant tumors

Significance of p53 in Cervical Cancer

Clinical Application Using p53

Findings

Conclusions