Top

Published in:

01-08-2012 | Preclinical Study

NFκB signaling is important for growth of antiestrogen resistant breast cancer cells

Authors: Christina W. Yde, Kristina B. Emdal, Barbara Guerra, Anne E. Lykkesfeldt

Published in: Breast Cancer Research and Treatment | Issue 1/2012

Abstract

Resistance to endocrine therapy is a major clinical challenge in current treatment of estrogen receptor-positive breast cancer. The molecular mechanisms underlying resistance are yet not fully clarified. In this study, we investigated whether NFκB signaling is causally involved in antiestrogen resistant cell growth and a potential target for re-sensitizing resistant cells to endocrine therapy. We used an MCF-7-derived cell model for antiestrogen resistant breast cancer to investigate dependence on NFκB signaling for antiestrogen resistant cell growth. We found that targeting NFκB preferentially inhibited resistant cell growth. Antiestrogen resistant cells expressed increased p50 and RelB, and displayed increased phosphorylation of p65 at Ser529 and Ser536. Moreover, transcriptional activity of NFκB after stimulation with tumor necrosis factor α was enhanced in antiestrogen resistant cell lines compared to the parental cell line. Inhibition of NFκB signaling sensitized tamoxifen resistant cells to the growth inhibitory effects of tamoxifen but was not sufficient to fully restore sensitivity of fulvestrant resistant cells to fulvestrant. In support of this, depletion of p65 with siRNA in tamoxifen resistant cells increased sensitivity to tamoxifen treatment. Our data provide evidence that NFκB signaling is enhanced in antiestrogen resistant breast cancer cells and plays an important role for antiestrogen resistant cell growth and for sensitivity to tamoxifen treatment in resistant cells. Our results imply that targeting NFκB might serve as a potential novel treatment strategy for breast cancer patients with resistance toward antiestrogen.

Ali S, Coombes RC (2002) Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2:101–112PubMedCrossRef

Croxtall JD, McKeage K (2011) Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women. Drugs 71:363–380PubMedCrossRef

Musgrove EA, Sutherland RL (2009) Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 9:631–643PubMedCrossRef

Ring A, Dowsett M (2004) Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11:643–658PubMedCrossRef

Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, Rasmussen LM, Riese DJ, de Cremoux P, Stenvang J, Lykkesfeldt AE (2009) Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat 114:263–275PubMedCrossRef

Frogne T, Laenkholm AV, Lyng MB, Henriksen KL, Lykkesfeldt AE (2009) Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor-positive tumors. Breast Cancer Res 11:R11PubMedCrossRef

Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, Wakeling AE, Nicholson RI (2003) Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells. Breast Cancer Res Treat 81:81–93PubMedCrossRef

Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE, Nicholson RI (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144:1032–1044PubMedCrossRef

McClelland RA, Barrow D, Madden TA, Dutkowski CM, Pamment J, Knowlden JM, Gee JM, Nicholson RI (2001) Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). Endocrinology 142:2776–2788PubMedCrossRef

10.

Nicholson RI, Johnston SR (2005) Endocrine therapy—current benefits and limitations. Breast Cancer Res Treat 93(Suppl 1):S3–S10PubMedCrossRef

11.

Gu Z, Lee RY, Skaar TC, Bouker KB, Welch JN, Lu J, Liu A, Zhu Y, Davis N, Leonessa F, Brunner N, Wang Y, Clarke R (2002) Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780). Cancer Res 62:3428–3437PubMed

12.

Nehra R, Riggins RB, Shajahan AN, Zwart A, Crawford AC, Clarke R (2010) BCL2 and CASP8 regulation by NF-kappaB differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and -resistant breast cancer cells. FASEB J 24:2040–2055PubMedCrossRef

13.

Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, Eppenberger U, Eppenberger-Castori S, Benz CC (2007) Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer 7:59PubMedCrossRef

14.

deGraffenried LA, Chandrasekar B, Friedrichs WE, Donzis E, Silva J, Hidalgo M, Freeman JW, Weiss GR (2004) NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen. Ann Oncol 15:885–890PubMedCrossRef

15.

Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96PubMedCrossRef

16.

Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18:2195–2224PubMedCrossRef

17.

Viatour P, Merville MP, Bours V, Chariot A (2005) Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci 30:43–52PubMedCrossRef

18.

Briand P, Lykkesfeldt AE (1984) Effect of estrogen and antiestrogen on the human breast cancer cell line MCF-7 adapted to growth at low serum concentration. Cancer Res 44:1114–1119PubMed

19.

Lykkesfeldt AE, Madsen MW, Briand P (1994) Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer Res 54:1587–1595PubMed

20.

Lykkesfeldt AE, Larsen SS, Briand P (1995) Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment. Int J Cancer 61:529–534PubMedCrossRef

21.

Lundholt BK, Briand P, Lykkesfeldt AE (2001) Growth inhibition and growth stimulation by estradiol of estrogen receptor transfected human breast epithelial cell lines involve different pathways. Breast Cancer Res Treat 67:199–214PubMedCrossRef

22.

Sonne-Hansen K, Norrie IC, Emdal KB, Benjaminsen RV, Frogne T, Christiansen IJ, Kirkegaard T, Lykkesfeldt AE (2010) Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance. Breast Cancer Res Treat 121:601–613PubMedCrossRef

23.

Dietrich N, Thastrup J, Holmberg C, Gyrd-Hansen M, Fehrenbacher N, Lademann U, Lerdrup M, Herdegen T, Jaattela M, Kallunki T (2004) JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways. Cell Death Differ 11:301–313PubMedCrossRef

24.

Yde CW, Olsen BB, Meek D, Watanabe N, Guerra B (2008) The regulatory beta-subunit of protein kinase CK2 regulates cell-cycle progression at the onset of mitosis. Oncogene 27:4986–4997PubMedCrossRef

25.

Waelchli R, Bollbuck B, Bruns C, Buhl T, Eder J, Feifel R, Hersperger R, Janser P, Revesz L, Zerwes HG, Schlapbach A (2006) Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. Bioorg Med Chem Lett 16:108–112PubMedCrossRef

26.

Zhou Y, Eppenberger-Castori S, Eppenberger U, Benz CC (2005) The NFkappaB pathway and endocrine-resistant breast cancer. Endocr Relat Cancer 12(Suppl 1):S37–S46PubMedCrossRef

27.

Shen HM, Tergaonkar V (2009) NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis 14:348–363PubMedCrossRef

28.

Madrid LV, Mayo MW, Reuther JY, Baldwin AS Jr (2001) Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 276:18934–18940PubMedCrossRef

29.

Frogne T, Jepsen JS, Larsen SS, Fog CK, Brockdorff BL, Lykkesfeldt AE (2005) Antiestrogen-resistant human breast cancer cells require activated protein kinase B/Akt for growth. Endocr Relat Cancer 12:599–614PubMedCrossRef

30.

Pradhan M, Bembinster LA, Baumgarten SC, Frasor J (2010) Proinflammatory cytokines enhance estrogen-dependent expression of the multidrug transporter gene ABCG2 through estrogen receptor and NF{kappa}B cooperativity at adjacent response elements. J Biol Chem 285:31100–31106PubMedCrossRef

31.

Nettles KW, Gil G, Nowak J, Métivier R, Sharma VB, Greene GL (2008) CBP Is a dosage-dependent regulator of nuclear factor-kappaB suppression by the estrogen receptor. Mol Endocrinol 22:263–272PubMedCrossRef

32.

Madsen MW, Reiter BE, Lykkesfeldt AE (1995) Differential expression of estrogen receptor mRNA splice variants in the tamoxifen resistant human breast cancer cell line, MCF-7/TAMR-1 compared to the parental MCF-7 cell line. Mol Cell Endocrinol 109:197–207PubMedCrossRef

33.

Larsen SS, Madsen MW, Jensen BL, Lykkesfeldt AE (1997) Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness. Int J Cancer 72:1129–1136PubMedCrossRef

34.

Cutrupi S, Reineri S, Panetto A, Grosso E, Caizzi L, Ricci L, Friard O, Agati S, Scatolini M, Chiorino G, Lykkesfeldt AE, De Bortoli M (2012) Targeting of the adaptor protein Tab 2 as a novel approach to revert tamoxifen resistance in breast cancer cells. Oncogene. doi:10.1038/onc.2011.627

35.

Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K (2000) TAB 2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 5:649–658PubMedCrossRef

36.

Riggins RB, Zwart A, Nehra R, Clarke R (2005) The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. Mol Cancer Ther 4:33–41PubMed

37.

Buss H, Dorrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M (2004) Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. J Biol Chem 279:55633–55643PubMedCrossRef

38.

Song YJ, Jen KY, Soni V, Kieff E, Cahir-McFarland E (2006) IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activation. Proc Natl Acad Sci USA 103:2689–2694PubMedCrossRef

39.

Wang D, Westerheide SD, Hanson JL, Baldwin AS Jr (2000) Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem 275:32592–32597PubMedCrossRef

40.

McElhinny JA, Trushin SA, Bren GD, Chester N, Paya CV (1996) Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, and T-291 and is required for its degradation. Mol Cell Biol 16:899–906PubMed

41.

Yde CW, Frogne T, Lykkesfeldt AE, Fichtner I, Issinger OG, Stenvang J (2007) Induction of cell death in antiestrogen resistant human breast cancer cells by the protein kinase CK2 inhibitor DMAT. Cancer Lett 256:229–237PubMedCrossRef

42.

Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F, Chalbos D, Sonenshein GE (2007) Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol 9:470–478PubMedCrossRef

Title: NFκB signaling is important for growth of antiestrogen resistant breast cancer cells
Authors: Christina W. Yde
Kristina B. Emdal
Barbara Guerra
Anne E. Lykkesfeldt
Publication date: 01-08-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2053-1

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

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Intraoperative ultrasound guidance for excision of non-palpable invasive breast cancer: a hospital-based series and an overview of the literature

Nuclear nano-morphology markers of histologically normal cells detect the “field effect” of breast cancer

Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival

Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor

111In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer

Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer