GPCR Modulation in Breast Cancer

Lappano, Rosamaria; Jacquot, Yves; Maggiolini, Marcello

doi:10.3390/ijms19123840

Cited by 38 publications

(27 citation statements)

References 262 publications

(316 reference statements)

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“…Given the appreciation of their role in cancer, the importance of GPCRs for anticancer drug discovery is undisputable, although very few members have been exploited in pursuit of anticancer therapies. In this study, we have confirmed the clinical value of GPSM2.Thus, GPSM2 may be a promising target for new cancer therapy through regulating GPCRs pathway (6,30). Due the value of GPSM2 in predicting disease recurrence, it would be better to add GPMS2 to the NGS panels like Oncotype Dx (31).…”

Section: Discussionsupporting

confidence: 65%

“…G-protein-coupled receptors (GPCRs) regulate numerous essential biological functions (3,4). The abnormal expression of GPCRs is associated with occurrence and development of diverse types of cancer, including breast cancer (5,6). GPSM2 (G protein signaling modulator 2) belongs to a protein family that regulates activation of G proteins (7), which then inhibit GPCR signaling by inhibiting GDP release from Gα subunits (8).…”

Section: Introductionmentioning

confidence: 99%

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Localization of GPSM2 in the Nucleus of Invasive Breast Cancer Cells Indicates a Poor Prognosis

et al. 2020

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Purpose: GPSM2 (G protein signaling modulator 2) was reported to be involved in the cell division of breast cancer cells. Additionally, cytoplasmic dynein may mediate the transport process of GPSM2. DYNC1I1 (Cytoplasmic dynein 1 intermediate chain 1) is the most common cargo-binding subunit of dynein. However, the relationship between GPSM2 and DYNC1I1 and its clinical value is unclear. Methods: Immunohistochemical staining was performed for assessment of GPSM2 and DYNC1I1 expression. Immunoprecipitation analysis was used to assess the interaction between GPSM2 and DYNC1I1. Results: GPSM2 was correlated with clinical characteristics of breast cancer patients and is an unfavorable independent prognostic factor. In addition, nuclear expression of GPSM2 is an unfavorable independent prognostic factor (HR = 2.658, 95% CI = 1.490-4.741, p = 0.001). GPSM2 and DYNC1I1 are known to form a complex in breast cancer cells. Patients who were positive for expression of both DYNC1I1 and GPSM2 presented with shorter recurrence-free survival than other patients. Importantly, patients with GPSM2 nuclear expression showed higher DYNC1I1 expression. Conclusion: GPSM2 was an independent prognostic factor in breast cancer and nuclear expression of GPSM2 was significantly associated with poor prognosis, which was related to the positive expression of DYNC1I1. Examination of both GPSM2 and DYNC1I1 is necessary to establish a prognosis in breast cancer patients.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Localization of GPSM2 in the Nucleus of Invasive Breast Cancer Cells Indicates a Poor Prognosis

et al. 2020

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“…In fact, ERα17p acts as an inverse agonist. As such, the motif PLMI could open new avenues for the synthesis of GPER disruptors, which offer hope, as do other GPCR inhibitors, for the treatment of breast cancer [80]. Our work also raises the question as to whether the 295–311 sequence of ERα could correspond to a recruitment platform with the GPER.…”

Section: Discussionmentioning

confidence: 93%

The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells

Lappano

Mallet

Rizzuti

et al. 2019

Cells

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The inhibition of the G protein-coupled estrogen receptor (GPER) offers promising perspectives for the treatment of breast tumors. A peptide corresponding to part of the hinge region/AF2 domain of the human estrogen receptor α (ERα17p, residues 295–311) exerts anti-proliferative effects in various breast cancer cells including those used as triple negative breast cancer (TNBC) models. As preliminary investigations have evoked a role for the GPER in the mechanism of action of this peptide, we focused our studies on this protein using SkBr3 breast cancer cells, which are ideal for GPER evaluation. ERα17p inhibits cell growth by targeting membrane signaling. Identified as a GPER inverse agonist, it co-localizes with GPER and induces the proteasome-dependent downregulation of GPER. It also decreases the level of pEGFR (phosphorylation of epidermal growth factor receptor), pERK1/2 (phosphorylation of extracellular signal-regulated kinase), and c-fos. ERα17p is rapidly distributed in mice after intra-peritoneal injection and is found primarily in the mammary glands. The N-terminal PLMI motif, which presents analogies with the GPER antagonist PBX1, reproduces the effect of the whole ERα17p. Thus, this motif seems to direct the action of the entire peptide, as highlighted by docking and molecular dynamics studies. Consequently, the tetrapeptide PLMI, which can be claimed as the first peptidic GPER disruptor, could open new avenues for specific GPER modulators.

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“…OR2T6 belongs to GPCRs, the largest family of cell-surface receptors. GPCRs have been proved to participate in the development and progression of many tumors including breast cancer (36). Consistently, GPCR-based drugs have shown promising efficacy in halting the tumor growth.…”

Section: Discussionmentioning

confidence: 99%

The Olfactory Receptor Family 2, Subfamily T, Member 6 (OR2T6) Is Involved in Breast Cancer Progression via Initiating Epithelial-Mesenchymal Transition and MAPK/ERK Pathway

Wang

et al. 2019

Front. Oncol.

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Breast cancer is the most common female malignancy worldwide, however its molecular pathogenesis still needs in-depth investigation. Here we first revealed that the olfactory receptor family 2, subfamily T, member 6 (OR2T6) was significantly over-expressed in breast cancer tissues compared with normal breast tissues. OR2T6 expression was tightly correlated with higher TNM staging, positive lymph node metastasis, and associated with poorer patients' overall and disease-free survival. And OR2T6 enhanced the proliferation, invasion, and migration ability of breast cancer cell lines in vitro (MCF-7 and MDA-MD-231). Mechanically, it promoted the expression of mesenchymal markers (Vimentin, N-cadherin, and β-catenin) while inhibited E-cadherin expression, suggesting that OR2T6 played a key role in the regulation of epithelial-mesenchymal transition (EMT) process. Moreover, the human gene expression microarray clarified that MAPK/ERK pathway could be initiated by OR2T6 at mRNA level, which was further confirmed at protein level by western blot analysis. Thus, we concluded that OR2T6, as a novel oncogene, contributed to the progression of breast carcinoma by the initiation of EMT and MAPK/ERK pathway.

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GPCR Modulation in Breast Cancer

Cited by 38 publications

References 262 publications

Localization of GPSM2 in the Nucleus of Invasive Breast Cancer Cells Indicates a Poor Prognosis

Localization of GPSM2 in the Nucleus of Invasive Breast Cancer Cells Indicates a Poor Prognosis

The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells

The Olfactory Receptor Family 2, Subfamily T, Member 6 (OR2T6) Is Involved in Breast Cancer Progression via Initiating Epithelial-Mesenchymal Transition and MAPK/ERK Pathway

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