Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro

Authors: Susanne Schüler-Toprak, Julia Häring, Elisabeth C. Inwald, Christoph Moehle, Olaf Ortmann, Oliver Treeck

Published in: BMC Cancer | Issue 1/2016

Login to get access

Abstract

Background

Estrogen receptor β (ERβ) is expressed in the majority of invasive breast cancer cases, irrespective of their subtype, including triple-negative breast cancer (TNBC). Thus, ERβ might be a potential target for therapy of this challenging cancer type. In this in vitro study, we examined the role of ERβ in invasion of two triple-negative breast cancer cell lines.

Methods

MDA-MB-231 and HS578T breast cancer cells were treated with the specific ERβ agonists ERB-041, WAY200070, Liquiritigenin and 3β-Adiol. Knockdown of ERβ expression was performed by means of siRNA transfection. Effects on cellular invasion were assessed in vitro by means of a modified Boyden chamber assay. Transcriptome analyses were performed using Affymetrix Human Gene 1.0 ST microarrays. Pathway and gene network analyses were performed by means of Genomatix and Ingenuity Pathway Analysis software.

Results

Invasiveness of MBA-MB-231 and HS578T breast cancer cells decreased after treatment with ERβ agonists ERB-041 and WAY200070. Agonists Liquiritigenin and 3β-Adiol only reduced invasion of MDA-MB-231 cells. Knockdown of ERβ expression increased invasiveness of MDA-MB-231 cells about 3-fold. Transcriptome and pathway analyses revealed that ERβ knockdown led to activation of TGFβ signalling and induced expression of a network of genes with functions in extracellular matrix, tumor cell invasion and vitamin D3 metabolism.

Conclusions

Our data suggest that ERβ suppresses invasiveness of triple-negative breast cancer cells in vitro. Whether ERβ agonists might be useful drugs in the treatment of triple-negative breast cancer, has to be evaluated in further animal and clinical studies.
Appendix
Available only for authorised users
Literature
1.
Morris GJ, Naidu S, Topham AK, Guiles F, Xu Y, McCue P, Schwartz GF, Park PK, Rosenberg AL, Brill K, et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Cancer. 2007;110(4):876–84.CrossRefPubMed
2.
Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006;24(36):5652–7.CrossRefPubMed
3.
Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol. 1998;16(8):2659–71.PubMed
4.
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329–34.CrossRefPubMed
5.
Wiggans RG, Woolley PV, Smythe T, Hoth D, Macdonald JS, Green L, Schein PS. Phase-II trial of tamoxifen in advanced breat cancer. Cancer Chemother Pharmacol. 1979;3(1):45–8.CrossRefPubMed
6.
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.CrossRefPubMed
7.
Bertucci F, Finetti P, Cervera N, Esterni B, Hermitte F, Viens P, Birnbaum D. How basal are triple-negative breast cancers? Int J Cancer. 2008;123(1):236–40.CrossRefPubMed
8.
Rakha EA, Elsheikh SE, Aleskandarany MA, Habashi HO, Green AR, Powe DG, El-Sayed ME, Benhasouna A, Brunet JS, Akslen LA, et al. Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res. 2009;15(7):2302–10.CrossRefPubMed
9.
Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, van de Vijver MJ. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007;9(5):R65.CrossRefPubMedPubMedCentral
10.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.CrossRefPubMed
11.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003;100(14):8418–23.CrossRefPubMedPubMedCentral
12.
Marotti JD, Collins LC, Hu R, Tamimi RM. Estrogen receptor-beta expression in invasive breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. Mod Pathol. 2010;23(2):197–204.CrossRefPubMed
13.
Treeck O, Lattrich C, Springwald A, Ortmann O. Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. Breast Cancer Res Treat. 2010;120(3):557–65.CrossRefPubMed
14.
Treeck O, Juhasz-Boess I, Lattrich C, Horn F, Goerse R, Ortmann O. Effects of exon-deleted estrogen receptor beta transcript variants on growth, apoptosis and gene expression of human breast cancer cell lines. Breast Cancer Res Treat. 2008;110(3):507–20.CrossRefPubMed
15.
Leygue E, Dotzlaw H, Watson PH, Murphy LC. Altered estrogen receptor alpha and beta messenger RNA expression during human breast tumorigenesis. Cancer Res. 1998;58(15):3197–201.PubMed
16.
Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004;64(1):423–8.CrossRefPubMed
17.
Skliris GP, Munot K, Bell SM, Carder PJ, Lane S, Horgan K, Lansdown MR, Parkes AT, Hanby AM, Markham AF, et al. Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol. 2003;201(2):213–20.CrossRefPubMed
18.
Sakamoto G, Honma N. Estrogen receptor-beta status influences clinical outcome of triple-negative breast cancer. Breast Cancer. 2009;16(4):281–2.CrossRefPubMed
19.
Lindberg K, Strom A, Lock JG, Gustafsson JA, Haldosen LA, Helguero LA. Expression of estrogen receptor beta increases integrin alpha1 and integrin beta1 levels and enhances adhesion of breast cancer cells. J Cell Physiol. 2010;222(1):156–67.CrossRefPubMed
20.
Thomas C, Rajapaksa G, Nikolos F, Hao R, Katchy A, McCollum CW, Bondesson M, Quinlan P, Thompson A, Krishnamurthy S, et al. ERbeta1 represses basal breast cancer epithelial to mesenchymal transition by destabilizing EGFR. Breast Cancer Res. 2012;14(6):R148.CrossRefPubMedPubMedCentral
21.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.CrossRefPubMed
22.
Guerini V, Sau D, Scaccianoce E, Rusmini P, Ciana P, Maggi A, Martini PG, Katzenellenbogen BS, Martini L, Motta M, et al. The androgen derivative 5alpha-androstane-3beta,17beta-diol inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype. Cancer Res. 2005;65(12):5445–53.CrossRefPubMed
23.
Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. Proc Natl Acad Sci U S A. 2002;99(21):13589–94.CrossRefPubMedPubMedCentral
24.
Pak TR, Chung WC, Lund TD, Hinds LR, Clay CM, Handa RJ. The androgen metabolite, 5alpha-androstane-3beta, 17beta-diol, is a potent modulator of estrogen receptor-beta1-mediated gene transcription in neuronal cells. Endocrinology. 2005;146(1):147–55.CrossRefPubMed
25.
Dondi D, Piccolella M, Biserni A, Della Torre S, Ramachandran B, Locatelli A, Rusmini P, Sau D, Caruso D, Maggi A, et al. Estrogen receptor beta and the progression of prostate cancer: role of 5alpha-androstane-3beta,17beta-diol. Endocr Relat Cancer. 2010;17(3):731–42.CrossRefPubMed
26.
Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, et al. Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Endocrinology. 2003;144(10):4241–9.CrossRefPubMed
27.
Harris HA. Preclinical characterization of selective estrogen receptor beta agonists: new insights into their therapeutic potential. Ernst Schering Found Symp Proc. 2006;1:149–61.
28.
Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith Jr JC, et al. Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands. J Med Chem. 2004;47(21):5021–40.CrossRefPubMed
29.
Mersereau JE, Levy N, Staub RE, Baggett S, Zogovic T, Chow S, Ricke WA, Tagliaferri M, Cohen I, Bjeldanes LF, et al. Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist. Mol Cell Endocrinol. 2008;283(1-2):49–57.CrossRefPubMed
30.
Lattrich C, Schuler S, Haring J, Skrzypczak M, Ortmann O, Treeck O. Effects of a combined treatment with tamoxifen and estrogen receptor beta agonists on human breast cancer cell lines. Arch Gynecol Obstet. 2014;289(1):163–71.CrossRefPubMed
31.
Lattrich C, Stegerer A, Haring J, Schuler S, Ortmann O, Treeck O. Estrogen receptor beta agonists affect growth and gene expression of human breast cancer cell lines. Steroids. 2013;78(2):195–202.CrossRefPubMed
32.
Uria JA, Jimenez MG, Balbin M, Freije JM, Lopez-Otin C. Differential effects of transforming growth factor-beta on the expression of collagenase-1 and collagenase-3 in human fibroblasts. J Biol Chem. 1998;273(16):9769–77.CrossRefPubMed
33.
Jinnin M, Ihn H, Asano Y, Yamane K, Trojanowska M, Tamaki K. Tenascin-C upregulation by transforming growth factor-beta in human dermal fibroblasts involves Smad3, Sp1, and Ets1. Oncogene. 2004;23(9):1656–67.CrossRefPubMed
34.
Choung J, Taylor L, Thomas K, Zhou X, Kagan H, Yang X, Polgar P. Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen alpha1, lysyl oxidase, and cyclooxygenase-1 genes in human embryo lung fibroblasts. J Cell Biochem. 1998;71(2):254–63.CrossRefPubMed
35.
Northey JJ, Dong Z, Ngan E, Kaplan A, Hardy WR, Pawson T, Siegel PM. Distinct phosphotyrosine-dependent functions of the ShcA adaptor protein are required for transforming growth factor beta (TGFbeta)-induced breast cancer cell migration, invasion, and metastasis. J Biol Chem. 2013;288(7):5210–22.CrossRefPubMed
36.
Wang Y, Lui WY. Transforming growth factor-beta1 attenuates junctional adhesion molecule-A and contributes to breast cancer cell invasion. Eur J Cancer. 2012;48(18):3475–87.CrossRefPubMed
37.
He Y, Northey JJ, Primeau M, Machado RD, Trembath R, Siegel PM, Lamarche-Vane N. CdGAP is required for transforming growth factor beta- and Neu/ErbB-2-induced breast cancer cell motility and invasion. Oncogene. 2011;30(9):1032–45.CrossRefPubMed
38.
Northey JJ, Chmielecki J, Ngan E, Russo C, Annis MG, Muller WJ, Siegel PM. Signaling through ShcA is required for transforming growth factor beta- and Neu/ErbB-2-induced breast cancer cell motility and invasion. Mol Cell Biol. 2008;28(10):3162–76.CrossRefPubMedPubMedCentral
39.
Ilunga K, Nishiura R, Inada H, El-Karef A, Imanaka-Yoshida K, Sakakura T, Yoshida T. Co-stimulation of human breast cancer cells with transforming growth factor-beta and tenascin-C enhances matrix metalloproteinase-9 expression and cancer cell invasion. Int J Exp Pathol. 2004;85(6):373–9.CrossRefPubMedPubMedCentral
40.
Albo D, Berger DH, Wang TN, Hu X, Rothman V, Tuszynski GP. Thrombospondin-1 and transforming growth factor-beta l promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system. Surgery. 1997;122(2):493–9. discussion 9-500.CrossRefPubMed
41.
Hirata E, Arakawa Y, Shirahata M, Yamaguchi M, Kishi Y, Okada T, Takahashi JA, Matsuda M, Hashimoto N. Endogenous tenascin-C enhances glioblastoma invasion with reactive change of surrounding brain tissue. Cancer Sci. 2009;100(8):1451–9.CrossRefPubMed
42.
Hancox RA, Allen MD, Holliday DL, Edwards DR, Pennington CJ, Guttery DS, Shaw JA, Walker RA, Pringle JH, Jones JL. Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms. Breast Cancer Res. 2009;11(2):R24.CrossRefPubMedPubMedCentral
43.
Sarkar S, Nuttall RK, Liu S, Edwards DR, Yong VW. Tenascin-C stimulates glioma cell invasion through matrix metalloproteinase-12. Cancer Res. 2006;66(24):11771–80.CrossRefPubMed
44.
Kaariainen E, Nummela P, Soikkeli J, Yin M, Lukk M, Jahkola T, Virolainen S, Ora A, Ukkonen E, Saksela O, et al. Switch to an invasive growth phase in melanoma is associated with tenascin-C, fibronectin, and procollagen-I forming specific channel structures for invasion. J Pathol. 2006;210(2):181–91.CrossRefPubMed
45.
Matsumoto K, Takahashi K, Yoshiki A, Kusakabe M, Ariga H. Invasion of melanoma in double knockout mice lacking tenascin-X and tenascin-C. Jpn J Cancer Res. 2002;93(9):968–75.CrossRefPubMed
46.
Jahkola T, Toivonen T, Virtanen I, von Smitten K, Nordling S, von Boguslawski K, Haglund C, Nevanlinna H, Blomqvist C. Tenascin-C expression in invasion border of early breast cancer: a predictor of local and distant recurrence. Br J Cancer. 1998;78(11):1507–13.CrossRefPubMedPubMedCentral
47.
Jahkola T, Toivonen T, Nordling S, von Smitten K, Virtanen I. Expression of tenascin-C in intraductal carcinoma of human breast: relationship to invasion. Eur J Cancer. 1998;34(11):1687–92.CrossRefPubMed
48.
Nielsen BS, Rank F, Lopez JM, Balbin M, Vizoso F, Lund LR, Dano K, Lopez-Otin C. Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas. Cancer Res. 2001;61(19):7091–100.PubMed
49.
Garcia-Quiroz J, Garcia-Becerra R, Barrera D, Santos N, Avila E, Ordaz-Rosado D, Rivas-Suarez M, Halhali A, Rodriguez P, Gamboa-Dominguez A, et al. Astemizole synergizes calcitriol antiproliferative activity by inhibiting CYP24A1 and upregulating VDR: a novel approach for breast cancer therapy. PLoS One. 2012;7(9):e45063.CrossRefPubMedPubMedCentral
50.
Lopes N, Sousa B, Martins D, Gomes M, Vieira D, Veronese LA, Milanezi F, Paredes J, Costa JL, Schmitt F. Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions. BMC Cancer. 2010;10:483.CrossRefPubMedPubMedCentral
51.
Lopes N, Paredes J, Costa JL, Ylstra B, Schmitt F. Vitamin D and the mammary gland: a review on its role in normal development and breast cancer. Breast Cancer Res. 2012;14(3):211.CrossRefPubMedPubMedCentral
52.
Shalhoub V, Shatzen EM, Ward SC, Young JI, Boedigheimer M, Twehues L, McNinch J, Scully S, Twomey B, Baker D, et al. Chondro/osteoblastic and cardiovascular gene modulation in human artery smooth muscle cells that calcify in the presence of phosphate and calcitriol or paricalcitol. J Cell Biochem. 2010;111(4):911–21.CrossRefPubMedPubMedCentral
53.
Pelicano H, Lu W, Zhou Y, Zhang W, Chen Z, Hu Y, Huang P. Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14-mediated mechanism. Cancer Res. 2009;69(6):2375–83.CrossRefPubMedPubMedCentral
54.
Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.CrossRefPubMed
55.
Takiguchi S, Korenaga N, Inoue K, Sugi E, Kataoka Y, Matsusue K, Futagami K, Li YJ, Kukita T, Teramoto N, et al. Involvement of CXCL14 in osteolytic bone metastasis from lung cancer. Int J Oncol. 2014;44(4):1316–24.PubMed
56.
Mokhtar NM, Cheng CW, Cook E, Bielby H, Smith SK, Charnock-Jones DS. Progestin regulates chemokine (C-X-C motif) ligand 14 transcript level in human endometrium. Mol Hum Reprod. 2010;16(3):170–7.CrossRefPubMed
57.
Frasor J, Danes JM, Funk CC, Katzenellenbogen BS. Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes. Proc Natl Acad Sci U S A. 2005;102(37):13153–7.CrossRefPubMedPubMedCentral
58.
Jenei-Lanzl Z, Straub RH, Dienstknecht T, Huber M, Hager M, Grassel S, Kujat R, Angele MK, Nerlich M, Angele P. Estradiol inhibits chondrogenic differentiation of mesenchymal stem cells via nonclassic signaling. Arthritis Rheum. 2010;62(4):1088–96.CrossRefPubMed
59.
Jeng MH, Jiang SY, Jordan VC. Paradoxical regulation of estrogen-dependent growth factor gene expression in estrogen receptor (ER)-negative human breast cancer cells stably expressing ER. Cancer Lett. 1994;82(2):123–8.CrossRefPubMed
60.
Finkelman RD, Bell NH, Strong DD, Demers LM, Baylink DJ. Ovariectomy selectively reduces the concentration of transforming growth factor beta in rat bone: implications for estrogen deficiency-associated bone loss. Proc Natl Acad Sci U S A. 1992;89(24):12190–3.CrossRefPubMedPubMedCentral
Metadata
Title
Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro
Authors
Susanne Schüler-Toprak
Julia Häring
Elisabeth C. Inwald
Christoph Moehle
Olaf Ortmann
Oliver Treeck
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2973-y

Other articles of this Issue 1/2016

BMC Cancer 1/2016 Go to the issue

Research article

Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program

Research article

Distinct genomic and epigenomic features demarcate hypomethylated blocks in colon cancer

Research article

EpCAM as multi-tumour target for near-infrared fluorescence guided surgery

Research article

MPO density in primary cancer biopsies of ovarian carcinoma enhances the indicative value of IL-17 for chemosensitivity

Research article

Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration

Study protocol

Role of geriatric intervention in the treatment of older patients with cancer: rationale and design of a phase III multicenter trial
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits