Role of GPR30 in endometrial pathology after tamoxifen for breast cancer

Ignatov, Tanja; Eggemann, Holm; Semczuk, Andrzej; Smith, Bobbie; Bischoff, Joachim; Roessner, Albert; Costa, Serban Dan; Kalinski, Thomas; Ignatov, Atanas

doi:10.1016/j.ajog.2010.07.034

Cited by 37 publications

(34 citation statements)

References 28 publications

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“…Filardo et al (2006) performed immunohistochemistry for GPR30 in 361 breast carcinomas and found that overexpression of GPR30 was significantly associated with tumor size ([2 cm), the presence of distant metastases, and HER-2/neu overexpression. Similar studies (Smith et al 2007;Ignatov et al 2010) have been conducted on tumors from patients with endometrial adenocarcinoma, and GPR30 overexpression has been found to occur more frequently in endometrial carcinomas exhibiting deep myometrial invasion, high grade, biologically aggressive histological subtype, advanced stage, and significantly worse overall survival rate. Interestingly, there was a significant correlation between G protein-coupled estrogen receptor expression and endometrial pathology in breast cancer patients receiving tamoxifen, an estrogen antagonist with antiproliferative properties in the breast but proliferative properties in the endometrium (Ignatov et al 2010).…”

Section: Discussionsupporting

confidence: 63%

“…Similar studies (Smith et al 2007;Ignatov et al 2010) have been conducted on tumors from patients with endometrial adenocarcinoma, and GPR30 overexpression has been found to occur more frequently in endometrial carcinomas exhibiting deep myometrial invasion, high grade, biologically aggressive histological subtype, advanced stage, and significantly worse overall survival rate. Interestingly, there was a significant correlation between G protein-coupled estrogen receptor expression and endometrial pathology in breast cancer patients receiving tamoxifen, an estrogen antagonist with antiproliferative properties in the breast but proliferative properties in the endometrium (Ignatov et al 2010). In the present study, we have demonstrated for the first time that GPR30 signaling in endometrial carcinoma cells enhances their tumorigenic capacity.…”

Section: Discussionsupporting

confidence: 63%

See 1 more Smart Citation

Estrogenic transmembrane receptor of GPR30 mediates invasion and carcinogenesis by endometrial cancer cell line RL95-2

Cai

et al. 2012

J Cancer Res Clin Oncol

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Section: Discussionsupporting

confidence: 63%

Section: Discussionsupporting

confidence: 63%

Estrogenic transmembrane receptor of GPR30 mediates invasion and carcinogenesis by endometrial cancer cell line RL95-2

Cai

et al. 2012

J Cancer Res Clin Oncol

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“…For example, it is now clear that fulvestrant lacks estrogen agonist effect to induce uterine weight and can fully block tamoxifen and estrogen induction of uterine weight. Nonetheless, multiple groups have reported data indicating that GPER activation can stimulate the proliferation of normal or malignant endometrial cells (Vivacqua et al, 2006;Dennis et al, 2009;Ignatov et al, 2010). Short-term acute dosing models examining more transient and refined responses may be better suited for clarifying the role of the GPER.…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

Fitts¹,

Klein²,

Powers³

2011

J Pharmacol Exp Ther

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Tamoxifen is a selective estrogen receptor (ER) modulator, but it is also a deactivating ligand for estrogen-related receptor-␥ (ERR␥) and a full agonist for the G protein-coupled estrogen receptor (GPER). Fulvestrant is a selective ER down-regulator that lacks agonist effects on ER␣/ER␤, is inactive on ERR␥, but acts as a full agonist on GPER. Fulvestrant effects on tamoxifen actions on uterine and somatic growth, bone, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and pituitary prolactin were analyzed to pharmacologically discriminate tamoxifen effects that may be mediated by ER␣/ER␤ versus ERR␥ versus GPER. Ovariectomized rats received tamoxifen (0.6 mg/kg/daily) plus fulvestrant at 0, 3, 6, or 12 mg/kg/daily for 5 weeks; controls received vehicle or 6 mg/kg fulvestrant daily. Tamoxifen effects to increase uterine weight, decrease serum IGF-I, increase pituitary prolactin, and increase bone mineral density could be fully blocked by fulvestrant, indicating mediation by ER␣/ER␤. Tamoxifen effects to decrease pituitary GH, tibia length, and body weight were only partially blocked by fulvestrant, indicating involvement of mechanisms unrelated to ER␣/ER␤. Fulvestrant did not inhibit tamoxifen actions to reduce total pituitary protein, again indicating effects not mediated by ER␣/ER␤. Tamoxifen actions to reduce serum GH were mimicked rather than inhibited by fulvestrant, pharmacological features consistent with GPER involvement. However, fulvestrant alone increased IGF-I and also blocked tamoxifen-evoked IGF-I decreases; thus fulvestrant effects on serum GH might reflect increased IGF-I feedback inhibition. Fulvestrant alone had no effect on the other parameters. The findings indicate that mechanisms unrelated to ER␣/ER␤ contribute to tamoxifen effects on body weight, bone growth, and pituitary function. IntroductionTamoxifen is an estrogen receptor (ER) ligand that is characterized as a selective ER modulator (SERM); it acts as estrogen agonist on some targets while acting as an antagonist or partial agonist on others. This is not attributed to differing pharmacological actions on ER␣ versus ER␤, but reflects the diversity of mechanisms mediating ER actions at different targets.In classic models of ER function, estrogen binding to the ligand-binding domain (LBD) transforms ER conformation and enhances ER binding to specific target gene DNA sequences (McDonnell et al., 2002;Smith and O'Malley, 2004). One or both of two ER transactivation domains (AF-1 and AF-2) then bind coactivator proteins that alter gene transcription via the recruitment of chromatin-remodeling complexes and other factors. AF-1 is located in the ER N terminus and is ligand-independent, whereas AF-2 in the LBD is ligand-dependent. Involvement of AF-1 or AF-2 in estrogen responses varies from target to target depending on the genes, cell types, coactivators, and other signaling systems involved.SERMs transform ER conformation in a manner that activates DNA binding and AF-1-dependent gene expression in classic models o...

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“…Immunohistochemistry GPR30 expression was analyzed as previously described [13]. Sections of formalin-fixed and paraffin-embedded breast cancer specimens or corresponding recurrent lesions (3.0 lm thick) were mounted on SuperFrost Plus glass slides (Menzel, Braunschweig, Germany) and dried overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Evaluation of GPR30 staining results GPR30 expression was classified as already described [13], according to the following grading system: staining extensity was categorized as 0 (no positive cells), 1 (\10% positive cells), 2 (10-50% positive cells), or 3 ([50% positive cells), and staining intensity was categorized as 0 (negative), 1 (weak), 2 (moderate), or 3 (strong). The individual categories were multiplied to give a total immunohistochemical score (IHC).…”

Section: Methodsmentioning

confidence: 99%

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

Ignatov

Weißenborn

et al. 2011

Breast Cancer Res Treat

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152

138

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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.

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Role of GPR30 in endometrial pathology after tamoxifen for breast cancer

Cited by 37 publications

References 28 publications

Estrogenic transmembrane receptor of GPR30 mediates invasion and carcinogenesis by endometrial cancer cell line RL95-2

Estrogenic transmembrane receptor of GPR30 mediates invasion and carcinogenesis by endometrial cancer cell line RL95-2

Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

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

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