Unique Molecular Features in High-Risk Histology Endometrial Cancers

Abstract

Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with endometrial cancer will develop high-risk histologic tumors including uterine carcinosarcoma or high-grade endometrioid, clear cell, or serous carcinomas. These high-risk histologic tumors account for more than 50% of deaths from this disease. In this review, we will highlight the biologic differences between low- and high-risk carcinomas with a focus on the cell of origin, early precursor lesions including atrophic and proliferative endometrium, and the potential role of stem cells. We will discuss treatment, including standard of care therapy, hormonal therapy, and precision medicine-based or targeted molecular therapies. We will also discuss the impact and need for model systems. The molecular underpinnings behind this high death to incidence ratio are important to understand and improve outcomes.

PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice

“…High-fidelity mouse models of poorlydifferentiated endometrial adenocarcinomas have not been described. Further, xenograft models have shown limited success for high-risk histologic endometrial adenocarcinoma types (22). Our findings indicate a relationship between appropriate miRNA expression, cell cycle control, and cell signaling pathways in the development of poorly-differentiated endometrial adenocarcinoma.…”

“…Poorly-differentiation endometrial tumors frequently develop within an atrophic, or postmenopausal endometrium (22). Pgr Cre/+; Dicer1 flox/flox mice have a benign single layer of luminal epithelium, lack of glandular epithelium, and thin to no endometrial stroma, a uterine phenotype consistent with atrophic endometrium from postmenopausal women (19).…”

“…Additional deletion of Pten in this background of Dicer1 deletion leads to poorlydifferentiated adenocarcinoma. While hyper-proliferation of endometrial epithelium from endogenous or exogenous estradiol with mutation of PTEN is a biologically plausible mechanism for the development of endometrial cancer (22), little is known about the mechanism of development of endometrial cancer from atrophic endometrium. In most dcKO mice, the tumors seemed to arise from individual areas of the uterus rather than homogenously along the entire uterus.…”

“…Treatment with progesterone did not alter the frequency of poorly-differentiated adenocarcinomas in ovex Pten cKO or dcKO mice ( Supplementary Table S2). Carefully selected women with well-differentiated, early-stage endometrioid adenocarcinoma can be treated with progesterone to preserve fertility options (22). Intact mice were randomized at six weeks to either placebo or progesterone pellet for 60 days.…”

“…To create an in vitro human model, CRISPR-Cas9 was used to delete DICER1 in Ishikawa cells, as they are PTEN mutant (22). Western blot confirmed knockdown or knockout of DICER1 ( Figure 4A).…”