Mechanisms and Consequences of PAX2 Inactivation in the Initiation of Endometrial Carcinogenesis - PROJECT SUMMARY/ABSTRACT Endometrial cancer represents 7% of all cancer and is the 4th most common cancer in women, with 68,000 new cases and 13,000 cancer-related deaths anticipated in 2024 in the USA. Annual deaths have been gradually increasing and are now anticipated to be higher than ovarian cancer. Although surgery can cure early-stage cancers, the 5-year survival of women with advanced endometrial cancer is <20%. These epidemiologic features should make an improved molecular understanding of endometrial cancer and new studies to achieve this goal a high priority. PAX2 is a paired box transcription factor expressed in the developing kidney and reproductive tract. PAX2 is required for the formation of the Müllerian duct, the embryonic structure which gives rise to the uterus and endometrium. High PAX2 expression is retained in normal endometrial glands throughout adult life. However, as we and others have shown, complete PAX2 loss occurs in >80% of all endometrial cancers, making it by far the most common known molecular feature of early and late endometrial cancers. More interestingly, PAX2 loss appears to be the initiating event as evidenced by 1) loss throughout most endometrial cancers 2) its equal prevalence in early endometrial precancers vs. fully-developed invasive or metastatic cancers and 3) the presence of rare PAX2-deficient glands in some normal endometria, arguing that these minute PAX2-null clones are the earliest precursors from which endometrial cancers arise. PAX2 mutations have not been identified in genome-wide analyses of endometrial cancer, nor have we found any in our preliminary studies. Thus, the mechanisms underlying PAX2 loss—and more importantly its functional consequences in instigating endometrial cancer—are critical questions demanding systematic investigation. We now propose to expand upon our prior clinical and laboratory observations through wide-ranging state-of-the-art methods to understand the basic mechanisms of PAX2 loss and its functional consequences in endometrial carcinogenesis. Our hypotheses are that 1) PAX2 undergoes repression by a specific epigenetic mechanism (gene silencing) and 2) PAX2 is a functional tumor suppressor through the regulation of the transcriptional landscape within the endometrial epithelial cells from which endometrial cancers arise. We will explore these hypotheses through diverse experiments aided by patient tumor specimens, cell line and animal models in a set of three integrated aims, undertaken by a fully committed team of investigators with complementary areas of expertise.
