Abstract 4211: Protein kinase C alpha (PKCα) signaling in endometrial cancer

Abstract

Endometrial cancer is the most common gynecological malignancy in the US and the fourth most common cancer in women. Despite its high incidence, there is limited knowledge of the molecular etiology of this disease. With obesity being a major risk factor, the incidence of endometrial cancer has been on a steady incline and is expected to become an increasing cause of cancer mortality in future years. Thus, improved understanding of endometrial tumorigenesis is of critical importance. Our analysis of human endometrial tumors identified loss of the signaling molecule PKCα in approximately 60% of endometrioid (Type I) tumors. Loss of PKCα trends with increasing tumor grade and is associated with aggressive disease features such as lymphovascular involvement and myometrial invasion, pointing to an important role for this molecule in regulating endometrial cancer progression. Inactivation of the tumor suppressor PTEN and deregulation of the PI3K/AKT pathway are key drivers of Type I endometrial cancer. Thus, mice with allele-specific knock-in of cancer-related Pten mutants (i.e., PtenΔ4-5, PtenC124R, and PtenG120E) offer unique models for the disease. Precancerous endometrial hyperplasias arising in these mice show loss of PTEN and increased AKT activity. While PKCα is expressed in the normal murine endometrial epithelium at all phases of the estrus cycle, the enzyme is uniformly lost in these precancerous lesions. Thus, disruption of PKCα signaling can occur early in endometrial tumorigenesis. In human endometrial cancer cell lines, low PKCα levels also correlate with PTEN loss; however, shRNA-mediated knockdown of PTEN in PTEN expressing cells did not affect PKCα expression indicating that downregulation of the kinase is not the direct result of changes in PTEN activity. Notably, PKC agonists suppress AKT activity in cells expressing high levels PKCα (HEC-1-A, HEC-50) but not in PKCα-low cells (Ishikawa, RL95-2). Collectively, these data suggest that, in addition to PTEN inactivation, loss of PKCα is required for full activation of the PI3K/AKT signaling pathway during endometrial carcinogenesis. Analysis of the molecular basis for loss of PKCα expression in endometrial tumors identified multiple regulatory mechanisms. PKCα protein expression in tumors generally parallels that of its mRNA and promoter activity assays point to transcriptional mechanisms for PKCα downregulation. Differential mRNA and protein stability were identified as additional levels of regulation of PKCα expression in endometrial cancer. Taken together, our findings indicate that 1) PKCα signaling regulates the PI3K/AKT pathway in the endometrial epithelium; 2) concomitant loss of PKCα and PTEN may act in a co-operative manner in regulation of endometrial turmorigenesis; and 3) loss of PKCα can occur by multiple mechanisms, as often seen with tumor suppressive molecules during neoplastic progression. Supported by NIH grants CA036727, CA016056, and DK60632. Citation Format: Alice H. Hsu, Kathryn J. Curry, Kang-Sup Shim, Peter Frederick, Carl D. Morrison, Baojing Chen, Subodh M. Lele, Gustavo Leone, Adrian R. Black, Jennifer D. Black. Protein kinase C alpha (PKCα) signaling in endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4211. doi:10.1158/1538-7445.AM2014-4211