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Published in: Clinical and Translational Oncology 9/2019

Open Access 01-09-2019 | Metastasis | Research Article

Elevated expression of GNAS promotes breast cancer cell proliferation and migration via the PI3K/AKT/Snail1/E-cadherin axis

Authors: X. Jin, L. Zhu, Z. Cui, J. Tang, M. Xie, G. Ren

Published in: Clinical and Translational Oncology | Issue 9/2019

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Abstract

Purpose

Although it has been well established that G protein plays pivotal roles in physiologic or pathologic conditions, including cancer formation, its role in breast cancer, especially specific subunits, remains largely unknown. Our work aimed to evaluate the correlation of the G protein alpha subunit (GNAS) with breast cancer and to investigate the underlying molecular mechanism.

Methods

The expression of GNAS was determined by breast tumor tissue microarray of 150 patients with complete follow-up information. The correlation between GNAS expression and clinical features was assessed. CCK8, EdU incorporation, flow cytometry, wound healing, transwell, western blot and tumor formation assays were carried out in nude mice to study the biological function of GNAS and the underlying molecular mechanism in breast cancer by silencing GNAS using a specific siRNA.

Results

High GNAS expression showed a close correlation with a reduced overall survival (p = 0.021), frequent distal metastasis (p = 0.026), advanced clinical stage (p = 0.001), stronger cell proliferation (ki67+ positive cell rate, p = 0.0351) and enhanced cancer cell migration, which was further confirmed by in vitro and in vivo assays and might be dependent on the PI3K/AKT/Snail1/E-cadherin axis.

Conclusion

The data suggested that GNAS promoted breast cancer cell proliferation and migration (EMT) through the PI3K/AKT/Snail1/E-cadherin signaling pathway. These findings also indicate that GNAS can serve as a potential prognostic indicator and novel therapeutic target in breast cancer.
Literature
1.
2.
go back to reference Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, et al. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009;69:4951.CrossRefPubMed Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, et al. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009;69:4951.CrossRefPubMed
4.
go back to reference Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov. 2011;10:47.CrossRefPubMed Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov. 2011;10:47.CrossRefPubMed
5.
6.
go back to reference O’Hayre M, Vázquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S, et al. The emerging mutational landscape of G-proteins and G-protein coupled receptors in cancer. Nat Rev Cancer. 2013;13:412.CrossRefPubMedPubMedCentral O’Hayre M, Vázquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S, et al. The emerging mutational landscape of G-proteins and G-protein coupled receptors in cancer. Nat Rev Cancer. 2013;13:412.CrossRefPubMedPubMedCentral
7.
go back to reference Lu C, Xia J, Zhou Y, Lu X, Zhang L, Gou M, et al. Loss of Gsα impairs liver regeneration through a defect in the crosstalk between cAMP and growth factor signaling. J Hepatol. 2016;64:342–51.CrossRefPubMed Lu C, Xia J, Zhou Y, Lu X, Zhang L, Gou M, et al. Loss of Gsα impairs liver regeneration through a defect in the crosstalk between cAMP and growth factor signaling. J Hepatol. 2016;64:342–51.CrossRefPubMed
8.
go back to reference Das R, Esposito V, Abu-Abed M, Anand GS, Taylor SS, Melacini G, et al. cAMP activation of PKA defines an ancient signaling mechanism. Proc Natl Acad Sci USA. 2007;104:93–8.CrossRefPubMed Das R, Esposito V, Abu-Abed M, Anand GS, Taylor SS, Melacini G, et al. cAMP activation of PKA defines an ancient signaling mechanism. Proc Natl Acad Sci USA. 2007;104:93–8.CrossRefPubMed
9.
go back to reference Beristain AG, Molyneux SD, Joshi PA, Pomroy NC, Di Grappa MA, Chang MC, et al. PKA signaling drives mammary tumorigenesis through Src. Oncogene. 2015;34:1160–73.CrossRefPubMed Beristain AG, Molyneux SD, Joshi PA, Pomroy NC, Di Grappa MA, Chang MC, et al. PKA signaling drives mammary tumorigenesis through Src. Oncogene. 2015;34:1160–73.CrossRefPubMed
10.
go back to reference Bhat RR, Yadav P, Sahay D, Bhargava DK, Creighton CJ, Yazdanfard S, et al. GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Research and Treatment. 2018;170(2):279–92.CrossRefPubMedPubMedCentral Bhat RR, Yadav P, Sahay D, Bhargava DK, Creighton CJ, Yazdanfard S, et al. GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Research and Treatment. 2018;170(2):279–92.CrossRefPubMedPubMedCentral
11.
go back to reference Rao A, Herr DR. G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells. Biochim Biophys Acta (BBA) Mol Cell Res. 2017;186:1318.CrossRef Rao A, Herr DR. G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells. Biochim Biophys Acta (BBA) Mol Cell Res. 2017;186:1318.CrossRef
12.
go back to reference Liang S, Chen Z, Jiang G, Zhou Y, Liu Q, Su Q, et al. Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-κB/IL-6 signals. Cancer Lett. 2017;386:12.CrossRefPubMed Liang S, Chen Z, Jiang G, Zhou Y, Liu Q, Su Q, et al. Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-κB/IL-6 signals. Cancer Lett. 2017;386:12.CrossRefPubMed
13.
go back to reference Chen M, Gavrilova O, Zhao WQ, Nguyen A, Lorenzo J, Shen L, et al. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gsalpha deficiency. J Clin Investig. 2005;115:3217–27.CrossRefPubMedPubMedCentral Chen M, Gavrilova O, Zhao WQ, Nguyen A, Lorenzo J, Shen L, et al. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gsalpha deficiency. J Clin Investig. 2005;115:3217–27.CrossRefPubMedPubMedCentral
15.
go back to reference Khalil BD, Hsueh C, Cao Y, Abi Saab WF, Wang Y, Condeelis JS, et al. GPCR signaling mediates tumor metastasis via PI3Kβ. Cancer Res. 2016;76:2944–53.CrossRefPubMedPubMedCentral Khalil BD, Hsueh C, Cao Y, Abi Saab WF, Wang Y, Condeelis JS, et al. GPCR signaling mediates tumor metastasis via PI3Kβ. Cancer Res. 2016;76:2944–53.CrossRefPubMedPubMedCentral
16.
go back to reference Donini CF, Di ZE, Zuchegna C, Di Domenico M, D’Inzeo S, Nicolussi A, et al. The p85α regulatory subunit of PI3K mediates cAMP-PKA and retinoic acid biological effects on MCF7 cell growth and migration. Int J Oncol. 2012;40:1627–35.PubMed Donini CF, Di ZE, Zuchegna C, Di Domenico M, D’Inzeo S, Nicolussi A, et al. The p85α regulatory subunit of PI3K mediates cAMP-PKA and retinoic acid biological effects on MCF7 cell growth and migration. Int J Oncol. 2012;40:1627–35.PubMed
17.
go back to reference Bill R, Christofori G. The relevance of EMT in breast cancer metastasis: correlation or causality? FEBS Lett. 2015;589:1577–87.CrossRefPubMed Bill R, Christofori G. The relevance of EMT in breast cancer metastasis: correlation or causality? FEBS Lett. 2015;589:1577–87.CrossRefPubMed
18.
go back to reference Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, et al. Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med. 2016;22:723–6.CrossRefPubMedPubMedCentral Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, et al. Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med. 2016;22:723–6.CrossRefPubMedPubMedCentral
19.
go back to reference Liu H, Murphy CJ, Karreth FA, Emdal KB, White FM, Elemento O, et al. Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple negative breast cancer. Cancer Discov. 2018;8:354–69.CrossRefPubMed Liu H, Murphy CJ, Karreth FA, Emdal KB, White FM, Elemento O, et al. Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple negative breast cancer. Cancer Discov. 2018;8:354–69.CrossRefPubMed
20.
22.
go back to reference Peters J, Holmes R, Monk D, Beechey CV, Moore GE, Williamson CM. Imprinting control within the compact Gnas locus. Cytogenet Genome Res. 2006;113:194–201.CrossRefPubMed Peters J, Holmes R, Monk D, Beechey CV, Moore GE, Williamson CM. Imprinting control within the compact Gnas locus. Cytogenet Genome Res. 2006;113:194–201.CrossRefPubMed
23.
go back to reference Mantovani G, Lania AG, Spada A. GNAS imprinting and pituitary tumors. Mol Cell Endocrinol. 2010;326:15–8.CrossRefPubMed Mantovani G, Lania AG, Spada A. GNAS imprinting and pituitary tumors. Mol Cell Endocrinol. 2010;326:15–8.CrossRefPubMed
24.
go back to reference Ideno N, Ohtsuka T, Matsunaga T, Kimura H, Watanabe Y, Tamura K, et al. Clinical significance of GNAS mutation in intraductal papillary mucinous neoplasm of the pancreas with concomitant pancreatic ductal adenocarcinoma. Pancreas. 2015;44:311.CrossRefPubMed Ideno N, Ohtsuka T, Matsunaga T, Kimura H, Watanabe Y, Tamura K, et al. Clinical significance of GNAS mutation in intraductal papillary mucinous neoplasm of the pancreas with concomitant pancreatic ductal adenocarcinoma. Pancreas. 2015;44:311.CrossRefPubMed
25.
go back to reference Ritterhouse LL, Vivero M, Mino-Kenudson M, Sholl LM, Iafrate AJ, Nardi V, et al. GNAS mutations in primary mucinous and non-mucinous lung adenocarcinomas. Mod Pathol. 2017;30:1720–7.CrossRefPubMed Ritterhouse LL, Vivero M, Mino-Kenudson M, Sholl LM, Iafrate AJ, Nardi V, et al. GNAS mutations in primary mucinous and non-mucinous lung adenocarcinomas. Mod Pathol. 2017;30:1720–7.CrossRefPubMed
26.
go back to reference Volckmar AL, Leichsenring J, Flechtenmacher C, Pfarr N, Siebolts U, Kirchner M, et al. Tubular, lactating, and ductal adenomas are devoid of MED12 Exon2 mutations, and ductal adenomas show recurrent mutations in GNAS and the PI3K–AKT pathway. Genes Chromosom Cancer. 2016;56:11–7.CrossRefPubMed Volckmar AL, Leichsenring J, Flechtenmacher C, Pfarr N, Siebolts U, Kirchner M, et al. Tubular, lactating, and ductal adenomas are devoid of MED12 Exon2 mutations, and ductal adenomas show recurrent mutations in GNAS and the PI3K–AKT pathway. Genes Chromosom Cancer. 2016;56:11–7.CrossRefPubMed
27.
go back to reference Garcia-Murillas I, Sharpe R, Pearson A, Campbell J, Natrajan R, Ashworth A, et al. An siRNA screen identifies the GNAS locus as a driver in 20q amplified breast cancer. Oncogene. 2013;33:2478–86.CrossRefPubMedPubMedCentral Garcia-Murillas I, Sharpe R, Pearson A, Campbell J, Natrajan R, Ashworth A, et al. An siRNA screen identifies the GNAS locus as a driver in 20q amplified breast cancer. Oncogene. 2013;33:2478–86.CrossRefPubMedPubMedCentral
28.
go back to reference Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46:372–83.CrossRefPubMed Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46:372–83.CrossRefPubMed
29.
go back to reference Law NC, White MF, Hunzickerdunn ME. G protein-coupled receptors (GPCRs) that signal via protein kinase A (PKA) cross-talk at insulin receptor substrate 1 (IRS1) to activate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. J Biol Chem. 2016;291:27160–9.CrossRefPubMedPubMedCentral Law NC, White MF, Hunzickerdunn ME. G protein-coupled receptors (GPCRs) that signal via protein kinase A (PKA) cross-talk at insulin receptor substrate 1 (IRS1) to activate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. J Biol Chem. 2016;291:27160–9.CrossRefPubMedPubMedCentral
30.
go back to reference Suire S, Lécureuil C, Anderson KE, Damoulakis G, Niewczas I, Davidson K, et al. GPCR activation of Ras and PI3Kc in neutrophils depends on PLCb2/b3 and the RasGEF RasGRP4. EMBO J. 2012;31:3118–29.CrossRefPubMedPubMedCentral Suire S, Lécureuil C, Anderson KE, Damoulakis G, Niewczas I, Davidson K, et al. GPCR activation of Ras and PI3Kc in neutrophils depends on PLCb2/b3 and the RasGEF RasGRP4. EMBO J. 2012;31:3118–29.CrossRefPubMedPubMedCentral
31.
go back to reference Law NC, White MF, Hunzickerdunn ME. G protein-coupled receptors (GPCRs) that signal via protein kinase A (PKA) cross-talk at insulin receptor substrate 1 (IRS1) to activate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. J Biol Chem. 2016;291(53):27160–9.CrossRefPubMedPubMedCentral Law NC, White MF, Hunzickerdunn ME. G protein-coupled receptors (GPCRs) that signal via protein kinase A (PKA) cross-talk at insulin receptor substrate 1 (IRS1) to activate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. J Biol Chem. 2016;291(53):27160–9.CrossRefPubMedPubMedCentral
32.
go back to reference Hunzickerdunn ME, Lopezbiladeau B, Law NC, Daniel WC, Carr DW, Maizels ET. PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells. Proc Natl Acad Sci U S A. 2012;109(44):17742–3. Hunzickerdunn ME, Lopezbiladeau B, Law NC, Daniel WC, Carr DW, Maizels ET. PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells. Proc Natl Acad Sci U S A. 2012;109(44):17742–3.
Metadata
Title
Elevated expression of GNAS promotes breast cancer cell proliferation and migration via the PI3K/AKT/Snail1/E-cadherin axis
Authors
X. Jin
L. Zhu
Z. Cui
J. Tang
M. Xie
G. Ren
Publication date
01-09-2019
Publisher
Springer International Publishing
Published in
Clinical and Translational Oncology / Issue 9/2019
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-019-02042-w

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