Inhibition of growth hormone receptor by Somavert reduces expression of GPER and prevents growth stimulation of triple‑negative breast cancer by 17β‑estradiol

Abstract

Abstract. Currently, conventional chemotherapy is the only treatment option for triple-negative breast cancers (TNBC) due to a lack of a unique target. In TNBC, a high expression of the membrane bound G protein-coupled estrogen receptor (GPER), correlates with a worse outcome. There is a potential for an association between growth hormone receptor (GHR) and GPER expression. To confirm this hypothesis, GHR was inhibited in TNBC cells with Somavert, and GPER expression levels, and the effect on signal transduction and proliferation induction in TNBC cells were analyzed. Proliferation of TNBC cells was measured using an Alamar-blue assay. Expression of GPER and activation of c-src and epidermal growth factor receptor (EGFR) by 17β-estradiol was analyzed by western blotting. Induction of c-fos, cyclin D1 and aromatase expression was determined by reverse transcription-semi-quantitative polymerase chain reaction. The expression of GPER was concentration-and time-dependently reduced by Somavert down to 46±7% (P<0.01) of the control. Furthermore, 17β-estradiol significantly increased the cell number of HCC1806 cells to 128±14% (P<0.05), and that of MDA-MB-453 cells to 115±3%. This increase in cell number was reduced to 103±11% in HCC1806 cells in which GPER expression was downregulated by Somavert, and to 102±3% in MDA-MB-453 cells. In addition, 17β-estradiol increased the activation of c-src in HCC1806 cells by 1.8-fold, and Somavert reduced p-src to 63% of control. In MDA-MB-453 cells src phosphorylation increased by 7-fold upon stimulation with estradiol, but after treatment with Somavert only a 4-fold increase was observed. Phosphorylation of EGFR was increased by 2.2-fold of control in HCC1806 cells by 17β-estradiol, and by 1.4-fold in MDA-MD-453 cells. Somavert completely prevented this activation. Induction of cyclin D1 and aromatase expression by 17β-estradiol was also prevented by Somavert. Somavert reduces GPER expression in triple negative breast cancer cells. Treatment with Somavert prevents induction of genes regulating proliferation by 17β-estradiol. Inhibition of GPER expression is a promising therapeutic intervention for TNBC.

Activation of GPER by E2 promotes proliferation, invasion and migration of breast cancer cells by regulating the miR‑124/CD151 pathway

“…Thus, it is important to investigate the effects of E2-GPER signaling on the proliferation, invasion and migration of breast cancer cells. A previous study reported that GPER expression is upregulated in patients with breast cancer ( 54 ). Another study indicated that E2-treated cancer-associated fibroblasts exhibit a positive feedback behavior, which involves GPER/EGFR/ERK signaling and E2 production, and contributes to the progression of breast cancer ( 55 ).…”

Role of G Protein-Coupled Estrogen Receptor in Cancer Progression

“…However, absence of GPER does not affect early tumor initiation or proliferation (30). GPER inhibitors, such as estriol (31) and gefitinib (32), and inhibition of GPER expression by inhibition of growth hormone receptor (33) prevent the 17β-estradiol-induced growth of TNBC. Furthermore, knockdown of ER-α36, which is induced by GPER, reduces estrogen resistance, proliferation, migration and invasion in breast cancer (28).…”

Novel insight into pancreatic adenocarcinoma pathogenesis using liquid association analysis

“…3 , genes in this triplet are involved in the cancer’s progression via "response to estradiol" biological process. It was also demonstrated that estrogens, like estradiol, are a major factor in the cancer’s progression, like breast cancer [ 68 ]. Additionally, these are tightly linked to the growth hormone (Gh/Gh1) [ 68 ].…”

“…It was also demonstrated that estrogens, like estradiol, are a major factor in the cancer’s progression, like breast cancer [ 68 ]. Additionally, these are tightly linked to the growth hormone (Gh/Gh1) [ 68 ].…”