G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer

Abstract

Recently, we have shown that the new G-protein-coupled estrogen receptor GPR30 plays an important role in the development of tamoxifen resistance in vitro. This study was undertaken to evaluate the correlation between GPR30 and tamoxifen resistance in breast cancer patients. GPR30 protein expression was evaluated by immunohistochemical analysis in 323 patients with primary operable breast cancer. The association between GPR30 expression and tamoxifen resistance was confirmed in a second cohort of 103 patients treated only with tamoxifen. Additionally, we evaluated GPR30 expression in 33 primary tumors and in recurrent tumors from the same patients. GPR30 expression was detected in 56.7% of the breast cancer specimens investigated and it correlated with overexpression of HER-2 (P = 0.021), EGFR (P = 0.024) and lymph node status (P = 0.047). In a first cohort, survival analysis showed that GPR30 was negatively correlated with relapse-free survival (RFS) only in patients treated with tamoxifen (tamoxifen with or without chemotherapy). GPR30 expression was associated with shorter RFS (HR = 1.768; 95% CI, 1.156-2.703; P = 0.009). In a subset of patients treated only with tamoxifen, multivariate analysis revealed that GPR30 expression is an independent unfavorable factor for RFS (HR = 4.440; 95% CI, 1.408-13.997; P = 0.011). In contrast, GPR30 tended to be a favorable factor regarding RFS in patients who did not receive tamoxifen. In 33 paired biopsies obtained before and after adjuvant therapy, GPR30 expression significantly increased only under tamoxifen treatment (P = 0.001). GPR30 expression in breast cancer independently predicts a poor RFS in patients treated with tamoxifen.

GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts

“…Likewise, estrogens have been shown to stimulate growth effects in tamoxifen-resistant breast cancer cells through both an increased expression of GPER1 and the GPER1-mediated transactivation of EGFR (Ignatov et al 2011). Notably, high levels of expression of GPER1 in breast, endometrial, and ovarian tumors have been associated with a higher risk of developing metastatic disease and poor survival rates (Prossnitz & Barton 2011).…”

GPER-1 acts as a tumor suppressor in ovarian cancer

“…Immunohistochemistry GPER-1 expression was analyzed as previously described [18]. Briefly, sections of formalin-fixed and paraffinembedded ovarian tumors, including benign ovarian cyst, tumors of low malignant potential (LMP) and malignant ovarian cancer specimens were investigated.…”

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

“…L'effet agoniste du tamoxifène sur ce récepteur pourrait intervenir dans les phénomènes de résistance (Maggiolini et al, 2004 ;Thomas et al, 2005 ;Pandey et al, 2009) et les effets indésirables au niveau de l'utérus (Henic et al, 2009 ;Vivacqua et al, 2006b) observés chez les patientes avec un cancer du sein. De ce fait, son expression dans des tumeurs mammaires de patientes traitées au tamoxifène serait un facteur de mauvais pronostic (Ignatov et al, 2011).…”

“…La présence du GPR30 a également été reportée comme une cause potentielle de ces résistances (Ignatov et al, 2011). En effet, le tamoxifène est un agoniste du GPR30 et induit l'expression de gènes impliqués dans la croissance cellulaire.…”