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

Abstract

Breast cancer is one of the most common malignancies worldwide and is responsible for a high mortality rate. However, the underlying pathological mechanism of breast cancer remains unclear. MicroRNAs (miRNAs/miRs) play critical roles in the progression of breast cancer. Recent studies have reported that miR-124/CD151 participates in the development of breast cancer. However, the exact molecular mechanism of miR-124/CD151 action in 17β-estradiol (E2)-treated breast cancer cells remains unknown. Thus, the present study aimed to investigate miR-124 and CD151 expression levels in MCF-7 cells treated with E2 via reverse transcription-quantitative PCR and western blot analyses. Bioinformatic analysis was performed to predict and identify whether CD151 is a potential target of miR-124. The Cell Counting Kit-8 and colony formation assays were performed to detect proliferation of MCF-7 cells. In addition, the invasive and migratory abilities of MCF-7 cells were assessed via the Transwell and wound healing assays, respectively. The results demonstrated that E2 downregulated miR-124 expression, while upregulating G protein -coupled estrogen receptor (GPER) expression in MCF-7 cells. Following treatment with the GPER antagonist, G15, miR-124 expression was significantly enhanced and E2-induced proliferation, invasion and migration of MCF-7 cells were notably inhibited. In addition, CD151 was confirmed as a direct target of miR-124. CD151 silencing remarkably suppressed the proliferation, invasion and migration of E2-induced MCF-7 cells. Taken together, these results suggest that upregulation of GPER expression induced by E2 promotes proliferation, invasion and migration of breast cancer cells by regulating the miR-124/CD151 pathway. Thus, the results of the present study provide a potential novel method for the treatment and prognosis of breast cancer.

Estrogen Receptors-Mediated Apoptosis in Hormone-Dependent Cancers

“…Particularly, GPER activation by E2 and/or specific ligand of GPER, G1 [75], determines multiple intracellular events such as EGFR transactivation leading to rapid ERK1/2 activation, PLC and PI3K phosphorylation, AC stimulation, and intracellular calcium mobilization [37,69,[76][77][78] involved in cell proliferation and apoptosis modulation [38][39][40]79]. GPER involvement in breast [80,81], endometrial [82], and ovarian [83] cancer progression has been reported. However, studies demonstrated that it can mediate anti-proliferative effects also in BC [79], PC [84], and OC [85] and can induce apoptosis in LCT [38] and ACC [40] cell lines.…”

Obesity as a Risk Factor for Breast Cancer—The Role of miRNA

“…The additional layer of the regulation of E2 genomic action is the interaction of ERs with various coactivators (CoA), such as transcription factor Sp1 (SP1), which modulate the binding of activated E2-ER complex with ERS [ 136 ]. Non-genomic action of E2 via binding to GPER1 leads to signal transduction through the G protein, which results in the synthesis of cAMP [ 137 , 138 , 139 ] and activation of downstream signaling pathways: phosphatidylinositol 3-kinase (PI3K), Akt kinase, Ca 2+ signaling, and MAP kinases [ 140 ]. In breast tumors, estrogenic activation of GPER1 leads to the induction of proliferation, migration, or angiogenesis [ 141 , 142 ].…”

“…Results presented by Yang H. and co-workers are important examples of cross-talk between miRNAs and ER signaling, as in their study, E2 decreased the expression of miR-124, while increasing GPER1 expression in MCF-7 cells. GPER-E2 signaling suppressed miR-124 and led to overexpression of CD151, and in addition, promoted proliferation, invasion, and migration of breast cancer cells [ 137 ]. This interplay between ERα, GPER1, and miRNAs is an important element of resistance to anti-estrogen therapy since it has been demonstrated that antagonists of the Erα, such as tamoxifen or fulvestrant, may activate GPER1 [ 164 ].…”

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

“…In addition, GPER activation has been observed to play a critical role in breast cancer growth, proliferation, migration, and metastasis [ 76 ] via the modulation of different molecular pathways. These include the stabilization of the F-actin cytoskeleton and the upregulation of Yes-Associated Protein 1 (YAP) and Transcriptional coactivator with a PDZ-binding domain (TAZ) via the activation of Gαq-11, Phospholipase C beta (PLCβ)/PKC and Rho/Rho-associated protein kinase (ROCK) signaling [ 87 , 88 ]; the downregulation of microRNA-124 (miR124) and miR-148a to promote proliferation and support immune invasion via the upregulation of CD151, HOX Transcript Antisense RNA (HOTAIR) and Histocompatibility Antigen, class I, G (HLA-G) [ 89 , 90 , 91 ]; the enhancement of Fibronectin (FN) matrix assembly and anchorage-independent growth [ 92 ]; and cell survival through the activation of epidermal growth factor receptor (EGFR)/ERK/c-Fos/Activator Protein 1 (AP-1) for Sirtuin 1 (SIRT1, also known as NAD-dependent deacetylase sirtuin-1) upregulation [ 93 ], MAPK/ERK/Tripartite Motif Containing 2 (TRIM-2) for Bcl-2-like protein 11 (BIM) downregulation [ 94 ], and EGFR/PI3K for Forkhead Box O3s (FOXO3a) inhibition [ 95 ]. Moreover, GPER appears to be required for stemness maintenance in cancer stem cells via PKA/Bcl-2 associated agonist of cell death (BAD) pathway [ 96 ] and the development of chemoresistance via EGFR/ERK/Akt-mediated ATP Binding Cassette, Subfamily G, Member 2 (ABCG2) expression [ 97 ].…”