Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis

Key Points Endometrial cancer is the most common gynaecological malignancy. Although no specific gene or genes have been linked to the majority of cases of endometrial cancer, several well-characterized oncogenes and tumour-suppressor genes have been implicated in endometrial carcinogenesis. Approximately 80% of endometrial cancer cases are type I tumours, which are usually well differentiated and endometrioid in histology, and are associated with a history of unopposed oestrogen exposure or other hyperoestrogenic risk factors such as obesity. Oestrogen and selective oestrogen-receptor modulators (SERMs) are implicated in endometrial carcinogenesis through regulation of gene transcription. Oestrogen and SERMs exert their carcinogenic roles in the endometrium through their downstream molecular effectors such as PAX2 (paired box gene 2). Both oestrogen and selective oestrogen receptor modulators can promote endometrial carcinogenesis. However, gene-expression studies have shown that they function through distinct, albeit overlapping, mechanisms. This article reviews our current understanding of both pathways. Endometrial cancer is the most common gynaecological cancer, and is associated with endometrial hyperplasia, unopposed oestrogen exposure and adjuvant therapy for breast cancer using selective oestrogen-receptor modulators (SERMs), particularly tamoxifen. Oestrogen and SERMs are thought to be involved in endometrial carcinogenesis through their effects on transcriptional regulation. Ultimately, oestrogen and SERMs affect the transduction of cellular signalling pathways that govern cell growth and proliferation, through downstream effectors such as PAX2 (paired box 2).