cancer may be the most common gynaecological malignancy in the Western world and its incidence is rising in most European countries mainly owing to increasing obesity. (2012) in this issue of the takes tissue biomarker studies a substantial step forward in endometrial cancer. The study was DZNep adequately powered with a primary set of 182 cases validated in a separate set of 474 cases and further confirmed by RNA expression in 237 cases where fresh tissue was available thus conforming to the REMARK guidelines. The authors evaluated the relative contributions to prognosis of the classical nuclear steroid receptor ERand the novel G-protein-coupled oestrogen receptor (GPER) in primary endometrial cancer. ERand ERpredominantly function through genomic signalling events while GPER stimulates EGFR ERK1/2 and PI3K through a non-genomic rapid signalling mechanism leading to widespread effects on neuroendocrine immune and reproductive functions. Since the discovery of ERin 1996 the field of oestrogen signalling has become increasingly complex. DZNep Oestrogen has many important functions both as a locally synthesised hormone in the reproductive organs and as a circulating transcription factor. The repertoire of functional oestrogen receptors now includes several splice variants which modify the effect of the classical receptors and/or provide alternative routes to transcriptional activation (Taylor expression. Loss of GPER also conferred a poor prognosis when the analysis was restricted to the ERpositive and the endometrioid histology subgroups. The double-negative GPER and ERsubgroup had the worst prognosis and the majority of metastases also showed loss of either GPER or ERexpression. The majority of the patients in this study were of low grade and endometrioid histology and within DZNep this subgroup these biomarkers are clearly useful in identifying a poor prognostic category. No information is given on treatments given to these patients and those studies where this is available have generally had small numbers of patients (Decruze and Green 2007 The authors provided some evidence based on RNA profiles supporting the use of HDAC inhibitors in ER+/GPER? endometrial DZNep cancers. However combinations either with conventional PP2Bgamma agents or additional targeted therapies are likely to be necessary to have a major impact on first-line therapy. In a study of 24 uterine carcinosarcomas Huang (2010) DZNep DZNep demonstrated a correlation between ERand GPER with higher expression in advanced stage disease. A further small study (Smith et al 2007 showed increased GPER was an unfavourable prognostic factor in keeping with studies in breast cancer. Clearly confirmation is required from centres or networks with adequate numbers of patients across the spectrum of uterine cancers. Ideally biomarkers should be assessed in tissue from relapsed patients as recent studies in other tumour types have confirmed extensive molecular heterogeneity between primary tumours and metastases (Gerlinger et al 2012 In endometrial cancer several years may elapse between initial diagnosis and instigation of systemic therapy. Non-squamous gynaecological cancers are heterogeneous and the pathogenesis of these cancers has recently been reviewed (Kurman and Shih 2010 Molecular similarity between endometrioid tumours arising from the endometrium and from the ovary leads to intriguing possibilities for selective approaches to treatment based on mutation profiles rather than presumed tissue of origin. This paper proposes GPER as a biomarker in endometrial cancer which shows promise for incorporation into clinical practice although this is neither a rapid nor an inexpensive process. In the meantime assessment of the ER status should become routine in endometrial cancers where the criteria established in breast cancer will suffice for the present. Increasing treatment options in endometrial cancer make accurate histopathological categorisation and molecular profiling essential although predictive factors related to the EGFR/PI3K pathways have not been validated sufficiently for routine.