Carcinosarcoma (CS) of the uterus is a highly aggressive tumor composed of mixed malignant epithelial and mesenchymal components. Although these tumors are relatively uncommon, accounting for only 4-9% of all uterine cancers, they are associated with disproportionately higher mortality rates compared with other corpus malignancies. While the etiopathogenesis of CS remains poorly understood, these tumors share epidemiologic risk factors with endometrioid-type endometrial carcinomas, including obesity and exposure to selective estrogen receptor (ER) modulators. These observations support a potential role of dysregulated estrogen signaling in the development of this tumor.

Estrogen is a central regulator of growth, differentiation, and function of reproductive tissues, including the uterus. The classic ERs are comprised of the related nuclear hormone receptors ERα and ERβ, which are coexpressed in the ovary and uterus during fetal development. In the adult reproductive tract, ERβ expression decreases relative to ERα in the uterus, while both isoforms continue to be expressed in the ovary. The downstream effects of ER subtype signaling appear to be highly tissue specific, with opposing actions in different organs. For example, in the ovary, loss of ERβ expression has been implicated in the development of ovarian cancer, and in the prostate and breast, ERβ appears to oppose the proliferative activity of ERα. Conversely, ERβ overexpression has been implicated in the pathogenesis of endometriosis, a disease characterized by ectopic proliferation of endometrial tissue. In this disease, ERβ was found to be highly overexpressed in endometriotic stromal cells compared with normal endometrium. Furthermore, in ovarian endometriosis, the overexpression of ERβ was shown to disrupt autoregulatory feedback, resulting in increased local levels of estradiol and proinflammatory factors.

We have previously reported our novel findings regarding the prognostic value of ER subtype expression in uterine CS. ERα expression was associated with an approximate 70% reduced risk for death in univariate survival analysis. In contrast, ERβ expression was significantly elevated in uterine CS, compared with normal endometrium, and high ERβ expression was significantly associated with advanced-stage disease.

A novel intracellular 7-transmembrane G protein-coupled receptor 30 (GPR30), also known as the G protein-coupled ER, has been identified and characterized by our group and others. GPR30 has been shown to mediate cellular responses to estrogen, independent of ERα and ERβ. Of note, GPR30 is stimulated by not only estrogen, but also by tamoxifen (a prototypical selective ER modulator). Ligand stimulation of GPR30 results in cyclic AMP production and calcium mobilization as well as c-Src, mitogen-activated protein kinase (MAPK), and phosphatidyl inositol 3-kinase activation, mediated by epidermal growth factor receptor transactivation.

To examine the role of GPR30 in endometrial cancer, our group performed a cross-sectional analysis of GPR30 tumor expression in 47 patients with diverse histologic types of endometrial cancer. The findings demonstrated that GPR30 was overexpressed more frequently in high-risk tumors, including 3 CS evaluated in the study. In addition, GPR30 expression was significantly associated with clinical and pathological predictors of poor survival in endometrial cancer, such as surgical stage and myometrial invasion. Similarly, in a recent analysis of primary ovarian tumors, GPR30 expression was significantly associated with higher tumor grade and advanced stage, while in breast cancer, high GPR30 expression has been correlated with the presence of distant metastases.

GPR30 expression was not assessed in our prior CS studies, nor have data on GPR30 expression in this tumor type been reported in the literature. Given our observation of ERβ overexpression in CS, particularly those of advanced stage, and the association of GPR30 expression with biologically aggressive endometrial neoplasia, we hypothesized that these alternative ERs may be coordinately expressed in uterine CS, in association with disease progression. Therefore, the aim of the current study was to evaluate the expression of GPR30 in uterine CS and its relationship with ER isoform expression and clinical/pathological factors.