ERα36-GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jul 24

PMID 34299224

Citations 8

Authors

George Notas

Athanasios Panagiotopoulos

Rodanthi Vamvoukaki

Konstantina Kalyvianaki

Foteini Kiagiadaki

Alexandra Deli

Marilena Kampa

Elias Castanas

Affiliations

Soon will be listed here.

Abstract

Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.

Citing Articles

Endothelial oestrogen-myocardial cyclic guanosine monophosphate axis critically determines angiogenesis and cardiac performance during pressure overload.

Fukuma N, Tokiwa H, Numata G, Ueda K, Liu P, Tajima M Cardiovasc Res. 2024; 120(15):1884-1897.

PMID: 39259833 PMC: 11630045. DOI: 10.1093/cvr/cvae202.

Pig-Derived Probiotic YB-2 Alleviates Intestinal Inflammation and Intestinal Barrier Damage in Colitis Mice by Suppressing the TLR4/NF-κB Signaling Pathway.

Yin H, Wang C, Shuai Y, Xie Z, Liu J Animals (Basel). 2024; 14(13).

PMID: 38998101 PMC: 11240761. DOI: 10.3390/ani14131989.

Sex Differences in Colon Cancer: Genomic and Nongenomic Signalling of Oestrogen.

Harvey B, Harvey H Genes (Basel). 2023; 14(12).

PMID: 38137047 PMC: 10742859. DOI: 10.3390/genes14122225.

Different Expression Pattern of G Protein-Coupled Estrogen Receptor GPER1 in Esophageal Squamous Cell Carcinoma and Adenocarcinoma.

Liu J, Niu Y, Zhang B, Sun Q, Li H, Bai L Int J Mol Sci. 2023; 24(18).

PMID: 37762356 PMC: 10531045. DOI: 10.3390/ijms241814055.

Localisation of oestrogen receptors in stem cells and in stem cell-derived neurons of the mouse.

Davis D, Vajaria R, Delivopoulos E, Vasudevan N J Neuroendocrinol. 2022; 35(2):e13220.

PMID: 36510342 PMC: 10909416. DOI: 10.1111/jne.13220.

References

Maruthanila V, Elancheran R, Kunnumakkara A, Kabilan S, Kotoky J . Recent development of targeted approaches for the treatment of breast cancer. Breast Cancer. 2016; 24(2):191-219. DOI: 10.1007/s12282-016-0732-1. View

Kim Y, Han M, Oh S . The molecular mechanism for nuclear transport and its application. Anat Cell Biol. 2017; 50(2):77-85. PMC: 5509903. DOI: 10.5115/acb.2017.50.2.77. View

Wein L, Luen S, Savas P, Salgado R, Loi S . Checkpoint blockade in the treatment of breast cancer: current status and future directions. Br J Cancer. 2018; 119(1):4-11. PMC: 6035268. DOI: 10.1038/s41416-018-0126-6. View

To S, Knower K, Clyne C . Origins and actions of tumor necrosis factor α in postmenopausal breast cancer. J Interferon Cytokine Res. 2013; 33(7):335-45. DOI: 10.1089/jir.2012.0155. View

Lee L, Cao J, Deng H, Chen P, Gatalica Z, Wang Z . ER-alpha36, a novel variant of ER-alpha, is expressed in ER-positive and -negative human breast carcinomas. Anticancer Res. 2008; 28(1B):479-83. PMC: 2610490. View

Wang W, Nag S, Zhang R . Targeting the NFκB signaling pathways for breast cancer prevention and therapy. Curr Med Chem. 2014; 22(2):264-89. PMC: 6690202. DOI: 10.2174/0929867321666141106124315. View

Martin S, Lebot M, Sukkarn B, Ball G, Green A, Rakha E . Low expression of G protein-coupled oestrogen receptor 1 (GPER) is associated with adverse survival of breast cancer patients. Oncotarget. 2018; 9(40):25946-25956. PMC: 5995224. DOI: 10.18632/oncotarget.25408. View

Pelekanou V, Barlow W, Nahleh Z, Wasserman B, Lo Y, von Wahlde M . Tumor-Infiltrating Lymphocytes and PD-L1 Expression in Pre- and Posttreatment Breast Cancers in the SWOG S0800 Phase II Neoadjuvant Chemotherapy Trial. Mol Cancer Ther. 2018; 17(6):1324-1331. PMC: 6548451. DOI: 10.1158/1535-7163.MCT-17-1005. View

Watson C, Jeng Y, Hu G, Wozniak A, Bulayeva N, Guptarak J . Estrogen- and xenoestrogen-induced ERK signaling in pituitary tumor cells involves estrogen receptor-α interactions with G protein-αi and caveolin I. Steroids. 2012; 77(5):424-32. PMC: 3304022. DOI: 10.1016/j.steroids.2011.12.025. View

10.

Pelekanou V, Notas G, Kampa M, Tsentelierou E, Radojicic J, Leclercq G . ERα36, a new variant of the ERα is expressed in triple negative breast carcinomas and has a specific transcriptomic signature in breast cancer cell lines. Steroids. 2011; 77(10):928-34. DOI: 10.1016/j.steroids.2011.12.016. View

11.

Zheng Y, Zhang J, Xu Z, Sheng J, Zhang X, Wang H . Quantitative profiles of the mRNAs of ER-alpha and its novel variant ER-alpha36 in breast cancers and matched normal tissues. J Zhejiang Univ Sci B. 2010; 11(2):144-50. PMC: 2816318. DOI: 10.1631/jzus.B0900266. View

12.

Notas G, Kampa M, Castanas E . G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases. Front Endocrinol (Lausanne). 2020; 11:579420. PMC: 7564022. DOI: 10.3389/fendo.2020.579420. View

13.

Allen M, Jones L . The role of inflammation in progression of breast cancer: Friend or foe? (Review). Int J Oncol. 2015; 47(3):797-805. DOI: 10.3892/ijo.2015.3075. View

14.

Liang S, Chen Z, Jiang G, Zhou Y, Liu Q, Su Q . Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-κB/IL-6 signals. Cancer Lett. 2016; 386:12-23. DOI: 10.1016/j.canlet.2016.11.003. View

15.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

16.

Notas G, Nifli A, Kampa M, Pelekanou V, Alexaki V, Theodoropoulos P . Quercetin accumulates in nuclear structures and triggers specific gene expression in epithelial cells. J Nutr Biochem. 2011; 23(6):656-66. DOI: 10.1016/j.jnutbio.2011.03.010. View

17.

Bailey S, Miron P, Choi Y, Kochupurakkal B, Maulik G, Rodig S . NF-κB activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth. Mol Cancer Res. 2013; 12(3):408-420. PMC: 4026253. DOI: 10.1158/1541-7786.MCR-13-0206-T. View

18.

Boonyaratanakornkit V, Hamilton N, Marquez-Garban D, Pateetin P, McGowan E, Pietras R . Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer. Mol Cell Endocrinol. 2017; 466:51-72. PMC: 5878997. DOI: 10.1016/j.mce.2017.11.010. View

19.

Oida K, Matsuda A, Jung K, Xia Y, Jang H, Amagai Y . Nuclear factor-ĸB plays a critical role in both intrinsic and acquired resistance against endocrine therapy in human breast cancer cells. Sci Rep. 2014; 4:4057. PMC: 3925966. DOI: 10.1038/srep04057. View

20.

Ariazi E, Brailoiu E, Yerrum S, Shupp H, Slifker M, Cunliffe H . The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer Res. 2010; 70(3):1184-94. PMC: 2879282. DOI: 10.1158/0008-5472.CAN-09-3068. View