GPER deletion triggers inhibitory effects in triple negative breast cancer (TNBC) cells through the JNK/c-Jun/p53/Noxa transduction pathway.

The G protein-coupled estrogen receptor (GPER) mediates estrogen action in different pathophysiological conditions, including cancer. GPER expression and signaling have been found to join in the progression of triple-negative breast cancer (TNBC), even though controversial data have been reported. In present study, we aimed at providing new mechanistic and biological discoveries knocking out (KO) GPER expression by CRISPR/Cas9 technology in MDA-MB-231 TNBC cells.

The Ephrin tyrosine kinase a3 (EphA3) is a novel mediator of RAGE-prompted motility of breast cancer cells.

Background: The receptor for advanced glycation-end products (RAGE) and its ligands have been implicated in obesity and associated inflammatory processes as well as in metabolic alterations like diabetes. In addition, RAGE-mediated signaling has been reported to contribute to the metastatic progression of breast cancer (BC), although mechanistic insights are still required. Here, we provide novel findings regarding the transcriptomic landscape and the molecular events through which RAGE may prompt aggressive features in estrogen receptor (ER)-positive BC.

Whole-genome CRISPR screening identifies PI3K/AKT as a downstream component of the oncogenic GNAQ-focal adhesion kinase signaling circuitry.

G proteins and G protein-coupled receptors activate a diverse array of signal transduction pathways that promote cell growth and survival. Indeed, hot spot-activating mutations in GNAQ/GNA11, encoding Gαq proteins, are known to be driver oncogenes in uveal melanoma (UM), for which there are limited effective therapies currently available. Focal adhesion kinase (FAK) has been recently shown to be a central mediator of Gαq-driven signaling in UM, and as a result, is being explored clinically as a therapeutic target for UM, both alone and in combination therapies.

Metformin counteracts stimulatory effects induced by insulin in primary breast cancer cells.

Background: Metabolic disorders are associated with increased incidence, aggressive phenotype and poor outcome of breast cancer (BC) patients. For instance, hyperinsulinemia is an independent risk factor for BC and the insulin/insulin receptor (IR) axis is involved in BC growth and metastasis. Of note, the anti-diabetic metformin may be considered in comprehensive therapeutic approaches in BC on the basis of its antiproliferative effects obtained in diverse pre-clinical and clinical studies.

Focal Adhesion Kinase (FAK)-Hippo/YAP transduction signaling mediates the stimulatory effects exerted by S100A8/A9-RAGE system in triple-negative breast cancer (TNBC).

Background: Understanding the intricate signaling network involved in triple-negative breast cancer (TNBC) represents a challenge for developing novel therapeutic approaches. Here, we aim to provide novel mechanistic insights on the function of the S100A8/A9-RAGE system in TNBC.

Methods: TNM plot analyzer, Kaplan-Meier plotter, Meta-analysis, GEPIA2 and GOBO publicly available datasets were used to evaluate the clinical significance of S100A8/A9 and expression levels of S100A8/A9, RAGE and Filamin family members in breast cancer (BC) subtypes.

Assessment of androgen receptor, IGF-IR and insulin receptor expression in male patients with severe peripheral artery disease.

Background: Peripheral artery disease (PAD) of the lower limbs is a common condition that can affect quality of life. Androgen receptor (AR) can exert sex-specific effects on metabolic system, endothelial function and vascular tone. IGF-I receptor (IGF-IR) and insulin receptor (IR) may also be involved in the aforementioned functions.

Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts.

Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild-type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC.

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression.

Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis.

Correction: Rigiracciolo, D.C., et al., IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells. 2020, 9, 1010.

The authors wish to make the following changes to their paper [...

The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs).

Background: Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses.

IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells.

Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood.

Cancer associated fibroblasts: role in breast cancer and potential as therapeutic targets.

: Cancer associated fibroblasts (CAFs) are the largest population of stromal cells in breast tumors. Emerging evidence has suggested that CAFs are important players not only in fostering tumor growth and spread but also in altering the tumor response to therapeutic agents. On the basis of these observations, huge efforts have been made to exploit CAFs as potential targets for breast cancer therapy.

The G Protein-Coupled Estrogen Receptor (GPER) Expression Correlates with Pro-Metastatic Pathways in ER-Negative Breast Cancer: A Bioinformatics Analysis.

The G protein-coupled estrogen receptor (GPER, formerly known as GPR30) is a seven-transmembrane receptor that mediates estrogen signals in both normal and malignant cells. In particular, GPER has been involved in the activation of diverse signaling pathways toward transcriptional and biological responses that characterize the progression of breast cancer (BC). In this context, a correlation between GPER expression and worse clinical-pathological features of BC has been suggested, although controversial data have also been reported.

GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression.

The FGF2/FGFR1 paracrine loop is involved in the cross-talk between breast cancer cells and components of the tumor stroma as cancer-associated fibroblasts (CAFs). By quantitative PCR (qPCR), western blot, immunofluorescence analysis, ELISA and ChIP assays, we demonstrated that 17β-estradiol (E2) and the G protein estrogen receptor (GPER) agonist G-1 induce the up-regulation and secretion of FGF2 via GPER together with the EGFR/ERK/c-fos/AP-1 signaling cascade in (ER)-negative primary CAFs. Evaluating the genetic alterations from METABRIC and TCGA datasets, we then assessed that FGFR1 is the most frequently amplified FGFRs family member and its amplification/expression associates with shorter survival rates in breast cancer patients.

A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK.

Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation.

Focal adhesion kinase (FAK) activation by estrogens involves GPER in triple-negative breast cancer cells.

Background: Focal adhesion kinase (FAK) is a cytoplasmatic protein tyrosine kinase that associates with both integrins and growth factor receptors toward the adhesion, migration and invasion of cancer cells. The G-protein coupled estrogen receptor (GPER) has been involved in the stimulatory action of estrogens in breast tumor. In this study, we have investigated the engagement of FAK by GPER signaling in triple negative breast cancer (TNBC) cells.

miR-338-3p Is Regulated by Estrogens through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts (CAFs).

Estrogens acting through the classic estrogen receptors (ERs) and the G protein estrogen receptor (GPER) regulate the expression of diverse miRNAs, small sequences of non-coding RNA involved in several pathophysiological conditions, including breast cancer. In order to provide novel insights on miRNAs regulation by estrogens in breast tumor, we evaluated the expression of 754 miRNAs by TaqMan Array in ER-negative and GPER-positive SkBr3 breast cancer cells and cancer-associated fibroblasts (CAFs) upon 17β-estradiol (E2) treatment. Various miRNAs were regulated by E2 in a peculiar manner in SkBr3 cancer cells and CAFs, while miR-338-3p displayed a similar regulation in both cell types.

miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling.

Background: MicroRNA (miRNAs) are non-coding small RNA molecules that regulate gene expression by inhibiting the translation of target mRNAs. Among several dysregulated miRNAs in human cancer, the up-regulation of miR-221 has been associated with development of a variety of hematologic and solid malignancies. In this study, we investigated the involvement of miR-221 in breast cancer.

GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer.

The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both estrogen biosynthesis and metabolism. For instance, CYP1B1 catalyzes the hydroxylation of E2 leading to the production of 4-hydroxyestradiol that may act as a potent carcinogenic agent. In addition, CYP1B1 is overexpressed in different tumors including breast cancer.

The lauric acid-activated signaling prompts apoptosis in cancer cells.

The saturated medium-chain fatty-acid lauric acid (LA) has been associated to certain health-promoting benefits of coconut oil intake, including the improvement of the quality of life in breast cancer patients during chemotherapy. As it concerns the potential to hamper tumor growth, LA was shown to elicit inhibitory effects only in colon cancer cells. Here, we provide novel insights regarding the molecular mechanisms through which LA triggers antiproliferative and pro-apoptotic effects in both breast and endometrial cancer cells.

GPER, IGF-IR, and EGFR transduction signaling are involved in stimulatory effects of zinc in breast cancer cells and cancer-associated fibroblasts.

Zinc (Zn) is an essential trace mineral that contributes to the regulation of several cellular functions; however, it may be also implicated in the progression of breast cancer through different mechanisms. It has been largely reported that the classical estrogen receptor (ER), as well as the G protein estrogen receptor (GPER, previously known as GPR30) can exert a main role in the development of breast tumors. In the present study, we demonstrate that zinc chloride (ZnCl ) involves GPER in the activation of insulin-like growth factor receptor I (IGF-IR)/epidermal growth factor receptor (EGFR)-mediated signaling, which in turn triggers downstream pathways like ERK and AKT in breast cancer cells, and main components of the tumor microenvironment namely cancer-associated fibroblasts (CAFs).

GPER is involved in the stimulatory effects of aldosterone in breast cancer cells and breast tumor-derived endothelial cells.

Aldosterone induces relevant effects binding to the mineralcorticoid receptor (MR), which acts as a ligand-gated transcription factor. Alternate mechanisms can mediate the action of aldosterone such as the activation of epidermal growth factor receptor (EGFR), MAPK/ERK, transcription factors and ion channels. The G-protein estrogen receptor (GPER) has been involved in the stimulatory effects of estrogenic signalling in breast cancer.

Copper activates HIF-1α/GPER/VEGF signalling in cancer cells.

Copper promotes tumor angiogenesis, nevertheless the mechanisms involved remain to be fully understood. We have recently demonstrated that the G-protein estrogen receptor (GPER) cooperates with hypoxia inducible factor-1α (HIF-1α) toward the regulation of the pro-angiogenic factor VEGF. Here, we show that copper sulfate (CuSO4) induces the expression of HIF-1α as well as GPER and VEGF in breast and hepatic cancer cells through the activation of the EGFR/ERK/c-fos transduction pathway.