Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases

Singh, Anukriti; Nunes, Jessica J.; Ateeq, Bushra

doi:10.1016/j.ejphar.2015.05.011

Cited by 29 publications

(19 citation statements)

References 79 publications

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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%

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%

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

et al. 2020

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“…Signaling pathways have been previously shown to be highly interconnected, with multiple points of convergence, cross talk and feedback loops, and these pathways can activate or inhibit each other, depending on the context and on cellular conditions (32)(33)(34)(35)(36). A compensatory mechanism, due to the presence of other signaling pathways, could explain the absence of or decrease in the expression of phosphoproteins.…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

Lion¹,

Harlé²,

Salleron³

et al. 2016

Oncology Letters

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Abstract. Human epidermal growth factor 2 (HER2) is overexpressed in 15-20% of breast carcinomas. The overexpression of HER2 was previously associated with a poor prognosis until the development of the first anti-HER2 therapy, trastuzumab, which drastically improves the prognosis of HER2-overexpressing breast cancers. However, its mechanism of action remains not fully understood. Several studies have proposed that the behavior and mechanism of action of trastuzumab may be drastically altered in vitro and in vivo. The present study assesses the ability of trastuzumab to inhibit the phosphorylation of the key-proteins of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin and Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways in vitro, in breast cancer cell lines and in tumor biopsies obtained from patients treated with trastuzumab preoperative monotherapy as part of the Unicancer GEP04 RADHER phase II clinical trial. HER2-positive SKBR3 and HER2-negative MCF-7 cell lines were exposed to trastuzumab for 72 h. In total, 41 patients received trastuzumab alone for 6 weeks of preoperative treatment. Biopsies were collected at the baseline and at surgery. A total of 19 pairs of associated baseline and surgery tumor specimens were eligible for protein extraction and comparative phosphoprotein expression analysis, prior to and subsequent to treatment. The expression of phosphoproteins was quantitatively assessed using a multiplex immunoassay. In the SKBR3 cell line, a statistically significant decrease of the expression level of phosphorylated (p-)AKT, p-ribosomal protein S6 kinase B1, p-extracellular signal regulated kinase 1/2 and p-mitogen-activated protein kinase kinase 1 was observed after exposure to trastuzumab. In contrast, no statistically significant variations for levels expression of these phosphoproteins were observed in patients following treatment. The lack of downregulation of PI3K and MAPK pathways could probably be explained by the implementation of a predominant immunological mechanism of action for trastuzumab, a type of antibody-dependent cell-mediated toxicity, which has previously been reported in preoperative monotherapy settings. The present study confirms that trastuzumab involves various modes of action when assayed in vitro and used clinically.

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“…Malignant cancer cells are known to hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase blood supply, invade their surrounding tissues and disseminate to other organs. Increased GPCR expression has been observed in various cancers including breast cancer [ 23 ]. Herein we observe an overall increase in percentage of GPCRs from 7% of total proteins identified in HOS cells to 18% of total in the human metastatic143B cells (Fig CA in S1 File ).…”

Section: Resultsmentioning

confidence: 99%

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin

et al. 2017

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Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

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Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases

Cited by 29 publications

References 79 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

Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin

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