Back
 JBM  Vol.5 No.8 , August 2017
G Protein-Coupled Estrogen Receptor Is a Critical Regulator in Metastasis of Breast Cancer Cells
Abstract: Estrogen signaling via GPER in breast cancers has been intensively discussed over years, but the underlying molecular mechanism remains to be fully elucidated, especially for the transcriptional profiles of the GPER under estrogen stimulation. In this study, we evaluated the potential role GPER in regulating invasion of metastatic breast cancer cell line MDA-MB-231 via transcriptional way. First, with primary breast cancer tissue samples, we found that the expression of GPER significantly coordinated with another membrane receptor-CXCR1. Besides, the expression level of these two proteins was associated with the development of the primary breast cancers. Second, to dissect the cross talk between GPER and CXCR1, we further our studies to detect the activation of ERK, Akt and transcriptional factor NF-kB. We found that upon estrogen stimulation, the phosphorylation level of ERK and Akt were rapidly increased and then resulted in the activation and nucleus translocation of NF-kB. When we considered the sub-sequence of the NF-kB activation, we found the autocrine of IL-8 was boosted by stimulation of the estrogen and followed by the promoted invasion of the MDA-MB-231 cells. In conclusion, our data demonstrated the estrogen-mediated GPER stimulation would regulate the invasive activities of metastatic breast cancer cell line MDA-MB-231 coupled with another membrane receptor CXCR1 via transcriptional pathway, the cross talk between GPER and CXCR1 may be another target for breast cancer therapies.
Cite this paper: Gao, B. , Chen, P. and Jiang, Q. (2017) G Protein-Coupled Estrogen Receptor Is a Critical Regulator in Metastasis of Breast Cancer Cells. Journal of Biosciences and Medicines, 5, 127-140. doi: 10.4236/jbm.2017.58010.
References

[1]   Nilsson, S., Makela, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M. and Gustafsson, J.A. (2001) Mechanisms of Estrogen Action. Physiological Reviews, No. 81, 1535-1565.

[2]   Pike, M.C., Pearce, C.L. and Wu, A.H. (2004) Prevention of Cancers of the Breast, Endometrium and Ovary. Oncogene, No. 23, 6379-6391.
https://doi.org/10.1038/sj.onc.1207899

[3]   Bai, Z. and Gust, R. (2009) Breast Cancer, Estrogen Receptor and Ligands. Archiv der Pharmazie (Weinheim), No. 342, 133-149.
https://doi.org/10.1002/ardp.200800174

[4]   Zhang, Y.J., Wei, L.H., Wang, J.L. and Sun, T.Z. (2003) Role of Phosphatase PTEN in the Activation of Extracellular Signal-Regulated Kinases Induced by Estradiol in Endometrial Carcinoma Cells. Chinese Medical Journal, 116, 383-387.

[5]   Castoria, G., Migliaccio, A., Bilancio, A., Di Domenico, M., de Falco, A., Lombardi, M., Fiorentino, R., Varricchio, L., Barone, M.V. and Auricchio, F. (2001) PI3-Kinase in Concert with Src Promotes the S-Phase Entry of Oestradiol-Stimulated MCF-7 Cells. The EMBO Journal, 20, 6050-6059.
https://doi.org/10.1093/emboj/20.21.6050

[6]   Kumar, V. and Chambon, P. (1988) The Estrogen Receptor Binds to Its Responsive Element as a Ligand-Induced Homodimer. Cell, 55, 145-156.
https://doi.org/10.1016/0092-8674(88)90017-7

[7]   Tsai, S.Y., Tsai, M.J. and O’ Malley, B.W. (1989) Cooperative Binding of Steroid Hormone Receptors Contributes to Transcriptional Synergism at Target Enhancer Elements. Cell, 57, 443-448.
https://doi.org/10.1016/0092-8674(89)90919-7

[8]   Thomas, P., Pang, Y., Filardo, E.J. and Dong, J. (2005) Identity of an Estrogen Membrane Receptor Coupled to a G Protein in Human Breast Cancer Cells. Endocrinology, 146, 624-632.
https://doi.org/10.1210/en.2004-1064

[9]   Sirianni, R., Chimento, A., Ruggiero, G., De Luca, A., Lappano, R., Ando, S., et al. (2008) The Novel Estrogen Receptor GPR30 Mediates the Proliferative Effects Induced by 17-ß-Estradiol on Mouse Spermatogonial GC-1 Cell Line. Endocrinology, 149, 5043-5051.
https://doi.org/10.1210/en.2007-1593

[10]   Prossnitz, E.R. and Maggiolini, M. (2009) Mechanisms of Estrogen Signaling and Gene Expression via GPR30. Molecular and Cellular Endocrinology, 308, 32-38.
https://doi.org/10.1016/j.mce.2009.03.026

[11]   Maggiolini, M. and Picard, D. (2010) The Unfolding Stories of GPR30, a New Membrane-Bound Estrogen Receptor. Journal of Endocrinology, 204, 105-114.
https://doi.org/10.1677/JOE-09-0242

[12]   Filardo, E.J., Quinn, J.A., Bland, K.I. and Frackelton Jr., A.R. (2000) Estrogen-Induced Activation of Erk-1 and Erk-2 Requires the G Protein-Coupled Receptor Homolog, GPR30, and Occurs via Transactivation of the Epidermal Growth Factor Receptor through Release of HB-EGF. Molecular Endocrinology, 14, 1649-1660.
https://doi.org/10.1210/mend.14.10.0532

[13]   Filardo, E.J., Quinn, J.A., Frackelton Jr., A.R. and Bland, K.I. (2002) Estrogen Action via the G Protein Coupled Receptor, GPR30: Stimulation of Adenylyl Cyclase and c-AMP Mediated Attenuation of the Epidermal Growth Factor Receptor-to-MAPK Signaling Axis. Molecular Endocrinology, 16, 70-84.
https://doi.org/10.1210/mend.16.1.0758

[14]   Xie, K. (2001) Interleukin-8 and Human Cancer Biology. Cytokine & Growth Factor Reviews, 12, 375-391.
https://doi.org/10.1016/S1359-6101(01)00016-8

[15]   Matsuo, Y., Ochi, N., Sawai, H., Yasuda, A., Takahashi, H., Funahashi, H., Takeyama, H., Tong, Z. and Guha, S. (2009) CXCL8/IL-8 and CXCL12/SDF-1alpha Co-Operatively Promote Invasiveness and Angiogenesis in Pancreatic Cancer. International Journal of Cancer, 124, 853-861.
https://doi.org/10.1002/ijc.24040

[16]   Merritt, W.M., Lin, Y.G., Spannuth, W.A., Fletcher, M.S., Kamat, A.A., Han, L.Y., Landen, C.N., Jennings, N., De Geest, K., Langley, R.R., Villares, G., Sanguino, A., Lutgendorf, S.K., Lopez-Berestein, G., Bar-Eli, M.M. and Sood, A.K. (2008) Effect of Interleukin-8 Gene Silencing with Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth. Journal of the National Cancer Institute, 100, 359- 372.
https://doi.org/10.1093/jnci/djn024

[17]   Freund, A., Chauveau, C., Brouillet, J.-P., Lucas, A., Lacroix, M., Licznar, A., Vignon, F. and Lazennec, G. (2003) IL-8 Expression and Its Possible Relationship with Estrogen-Receptor-Negative Status of Breast Cancer Cells. Oncogene, 22, 256-265.
https://doi.org/10.1038/sj.onc.1206113

[18]   Holmes, W.E., Lee, J., Kuang, W.J., Rice, G.C. and Wood, W.I. (1991) Structure and Functional Expression of a Human Interleukin-8 Receptor. Science, 253, 1278-1280.
https://doi.org/10.1126/science.1840701

[19]   Murphy, P.M. and Tiffany, H.L. (1991) Cloning of a Complimentary DNA Encoding a Functional Human Interleukin-8 Receptor. Science, 253, 1280-1283.
https://doi.org/10.1126/science.1891716

[20]   Ginestier, C., Liu, S., Diebel, M.E., Korkaya, H., Luo, M., Brown, M., Wicinski, J., Cabaud, O., Charafe-Jauffret, E., Birnbaum, D., Guan, J.L., Dontu, G. and Wicha, M.S. (2010) CXCR1 Blockade Selectively Targets Human Breast Cancer Stem Cells In Vitro and in Xenografts. The Journal of Clinical Investigation, 120, 485-497.
https://doi.org/10.1172/JCI39397

[21]   Yoshida, A., Yoshida, S., Khalil, A.K., Ishibashi, T. and Inomata, H. (1998) Role of NF-kappaB-Mediated Interleukin-8 Expression in Intraocular Neovascularization. Investigative Ophthalmology & Visual Science, 39, 1097-1106.

[22]   Elliott, C.L., Allport, V.C., Loudon, J.A., Wu, G.D. and Bennett, P.R. (2001) Nuclear Factor-KappaB Is Essential for Up-Regulation of Interleukin-8 Expression in Human Amnion and Cervical Epithelial Cells. Molecular Human Reproduction, 7, 787-790. https://doi.org/10.1093/molehr/7.8.787

[23]   Filardo, E.J., Quinn, J.A., Bland, K.I. and Frackelton Jr., A.R. (2000) Estrogen-Induced Activation of Erk1 and Erk2 Requires the G-Protein-Coupled Receptor Homolog, GPR30, and Occurs via Transactivation of the Epidermal Growth Factor Receptor through Release of HB-EGF. Molecular Endocrinology, 14, 1649-1660.
https://doi.org/10.1210/mend.14.10.0532

[24]   Bhola, N.E. and Grandis, J.R. (2008) Crosstalk between G-Protein-Coupled Receptors and Epidermal Growth Factor Receptor in Cancer. Frontiers in Bioscience, 13, 1857-1865.
https://doi.org/10.2741/2805

[25]   Nadel, J.A. (2001) Role of Epidermal Growth Factor Receptor Activation in Regulating Mucin Synthesis. Respiratory Research, 2, 85-89.
https://doi.org/10.1186/rr43

[26]   O’Donnell, R.A., Richter, A., Ward, J., Angco, G., Mehta, A., et al. (2004) Expression of ErbB Receptors and Mucins in the Airways of Long Term Current Smokers. Thorax, 59, 1032-1040.
https://doi.org/10.1136/thx.2004.028043

[27]   Shao, M.X., Nakanaga, T. and Nadel, J.A. (2004) Cigarette Smoke Induces MUC5AC Mucin Overproduction via Tumor Necrosis Factor-A-Converting Enzyme in Human Airway Epithelial (NCI-H292) Cells. American Journal of Physiology-Lung Cellular and Molecular Physiology, 287, L420-L427.
https://doi.org/10.1152/ajplung.00019.2004

[28]   Takeyama, K., Jung, B., Shim, J.J., Burgel, P.R., Dao-Pick, T., et al. (2001) Activation of Epidermal Growth Factor Receptors Is Responsible for Mucin Synthesis Induced by Cigarette Smoke. American Journal of Physiology-Lung Cellular and Molecular Physiology, 280, L165-L172.

[29]   Ning, Y., Manegold, P.C., Hong, Y.K., Zhang, W., Pohl, A., Lurje, G., Winder, T., Yang, D., LaBonte, M.J., Wilson, P.M., Ladner, R.D. and Lenz, H.J. (2011) Interleu-kin-8 Is Associated with Proliferation, Migration, Angiogenesis and Chemosensitivity In Vitro and In Vivo in Colon Cancer Cell Line Models. International Journal of Cancer, 128, 2038-2049.
https://doi.org/10.1002/ijc.25562

[30]   Filardo, E.J., Quinn, J.A., Bland, K.I. and Frackelton Jr., A.R. (2000) Estrogen-Induced Activation of Erk1 and Erk2 Requires the G-Protein-Coupled Receptor Homolog, GPR30, and Occurs via Transactivation of the Epidermal Growth Factor Receptor through Release of HB-EGF. Molecular Endocrinology, 14, 1649-1660.
https://doi.org/10.1210/mend.14.10.0532

[31]   Thomas, P., Pang, Y., Filardo, E.J. and Dong, J. (2005) Identity of an Estrogen Membrane Receptor Coupled to a G Protein in Human Breast Cancer Cells. Endocrinology, 146, 624-632.
https://doi.org/10.1210/en.2004-1064

[32]   Brailoiu, E., et al. (2007) Distribution and Characterization of Estrogen Receptor G-Protein Coupled Receptor 30 in the Rat Central Nervous System. Journal of Endocrinology, 193, 311-321.
https://doi.org/10.1677/JOE-07-0017

[33]   Revankar, C.M., Cimino, D.F., Sklar, L.A., Arterburn, J.B. and Prossnitz, E.R. (2005) A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling. Science, 307, 1625-1630.
https://doi.org/10.1126/science.1106943

[34]   Filardo, E.J., et al. (2006) Distribution of GPR30, a Seven Membrane-Spanning Estrogen Receptor, in Primary Breast Cancer and Its Association with Clinicopathologic Determinants of Tumor Progression. Clinical Cancer Research, 12, 6359-6366. https://doi.org/10.1158/1078-0432.CCR-06-0860

[35]   Luo, H.-J., Luo, P., Yang, G.-L., Peng, Q.-L., Liu, M.-R. and Tu, G. (2011) G-Protein Coupled Estrogen Receptor 1 Expression in Primary Breast Cancers and Its Correlation with Clinicopathological Variables. Journal of Breast Cancer, 14, 185-190.
https://doi.org/10.4048/jbc.2011.14.3.185

 
 
Top