Breast cancer oestrogen independence mediated by BCAR1 or BCAR3 genes is transmitted through mechanisms distinct from the oestrogen receptor signalling pathway or the epidermal growth factor receptor signalling pathway

Breast Cancer Research

Koen J Dechering²  Marcel Smid¹  Jos Veldscholte¹  Arend Brinkman¹  Ton van Agthoven¹  Lambert CJ Dorssers¹ 

[1] Department of Pathology, Josephine Nefkens Institute, Rotterdam, The Netherlands;Target Discovery, N.V. Organon, Oss, The Netherlands

关键词: tamoxifen;    signal transduction;    gene expression profiling;    breast cancer;    anti-oestrogen;   

Others  :  1115080
DOI  :  10.1186/bcr954

 received in 2004-01-26, accepted in 2004-09-30,  发布年份 2004

【 摘 要 】

Introduction

Tamoxifen is effective for endocrine treatment of oestrogen receptor-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing oestrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, but their direct effect on breast cancer cell proliferation is not known. The aim of this study was to investigate the growth control mediated by these BCAR genes by gene expression profiling.

Methods

We have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF). A comparison with published gene expression data of cell models and breast tumours is made.

Results

Relatively few changes in gene expression were detected in the BCAR-transfected cells, in comparison with the extensive and distinct differences in gene expression induced by oestrogen or EGF. Both BCAR1 and BCAR3 regulate discrete sets of genes in these ZR-75-1-derived cells, indicating that the proliferation signalling proceeds along distinct pathways. Oestrogen-regulated genes in our cell model showed general concordance with reported data of cell models and gene expression association with oestrogen receptor status of breast tumours.

Conclusions

The direct comparison of the expression profiles of BCAR transfectants and oestrogen or EGF-stimulated cells strongly suggests that anti-oestrogen-resistant cell proliferation is not caused by alternative activation of the oestrogen receptor or by the epidermal growth factor receptor signalling pathway.

【 授权许可】

   
2004 Dorssers et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, et al.: The nuclear receptor superfamily: the second decade. Cell 1995, 83:835-839.
• [2]McDonnell DP, Norris JD: Connections and regulation of the human estrogen receptor. Science 2002, 296:1642-1644.
• [3]Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996, 93:5925-5930.
• [4]Mosselman S, Polman J, Dijkema R: ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett 1996, 392:49-53.
• [5]McDonnell DP, Connor CE, Wijayaratne A, Chang CY, Norris JD: Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators. Recent Prog Horm Res 2002, 57:295-316.
• [6]Speirs V: Oestrogen receptor beta in breast cancer: good, bad or still too early to tell? J Pathol 2002, 197:143-147.
• [7]Klijn JGM, Berns PMJJ, Schmitz PIM, Foekens JA: The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev 1992, 13:3-17.
• [8]Van Agthoven T, Timmermans M, Foekens JA, Dorssers LCJ, Henzen-Logmans SC: Differential expression of estrogen, progesterone, and epidermal growth factor receptors in normal, benign, and malignant human breast tissues using dual staining immunohistochemistry. Am J Pathol 1994, 144:1238-1246.
• [9]Simpson ER, Dowsett M: Aromatase and its inhibitors: significance for breast cancer therapy. Recent Prog Horm Res 2002, 57:317-338.
• [10]O'Regan RM, Jordan VC: The evolution of tamoxifen therapy in breast cancer: selective oestrogen-receptor modulators and downregulators. Lancet Oncol 2002, 3:207-214.
• [11]Clarke R, Leonessa F, Welch JN, Skaar TC: Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev 2001, 53:25-71.
• [12]Johnston SRD, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M: Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res 1995, 55:3331-3338.
• [13]Robertson JFR: Oestrogen receptor: a stable phenotype in breast cancer. Br J Cancer 1996, 73:5-12.
• [14]Graham JD, Bain DL, Richer JK, Jackson TA, Tung L, Horwitz KB: Nuclear receptor conformation, coregulators, and tamoxifen-resistant breast cancer. Steroids 2000, 65:579-584.
• [15]Dorssers LCJ, Van der Flier S, Brinkman A, Van Agthoven T, Veldscholte J, Berns EMJJ, Klijn JGM, Beex LVAM, Foekens JA: Tamoxifen resistance in breast cancer: elucidating mechanisms. Drugs 2001, 61:1721-1733.
• [16]Dorssers LCJ, Van Agthoven T, Dekker A, Van Agthoven TLA, Kok EM: Induction of antiestrogen resistance in human breast cancer cells by random insertional mutagenesis using defective retroviruses: identification of bcar-1, a common integration site. Mol Endocrinol 1993, 7:870-878.
• [17]Van Agthoven T, Van Agthoven TLA, Dekker A, Van der Spek PJ, Vreede L, Dorssers LCJ: Identification of BCAR3 by a random search for genes involved in antiestrogen resistance of human breast cancer cells. EMBO J 1998, 17:2799-2808.
• [18]Brinkman A, Van der Flier S, Kok EM, Dorssers LCJ: BCAR1, a human homologue of the adapter protein p130Cas and antiestrogen resistance in breast cancer cells. J Natl Cancer Inst 2000, 92:112-120.
• [19]O'Neill GM, Fashena SJ, Golemis EA: Integrin signalling: a new cas(t) of characters enters the stage. Trends Cell Biol 2000, 10:111-119.
• [20]Bouton AH, Riggins RB, Bruce-Staskal PJ: Functions of the adapter protein Cas: signal convergence and the determination of cellular responses. Oncogene 2001, 20:6448-6458.
• [21]Van der Flier S, Brinkman A, Look MP, Kok EM, Meijer-Van Gelder ME, Klijn JGM, Dorssers LCJ, Foekens JA: Bcar1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment. J Natl Cancer Inst 2000, 92:120-127.
• [22]Grebenchtchikov N, Brinkman A, Van Broekhoven SPJ, De Jong D, Geurts-Moespot A, Span PN, Peters HA, Portengen H, Foekens JA, Sweep CGJ, et al.: Development of an ELISA for measurement of BCAR1 protein in human breast cancer tissue. Clin Chem 2004, 50:1356-1363.
• [23]Dorssers LCJ, Grebenchtchikov N, Brinkman A, Look MP, Klijn JGM, Geurts-Moespot A, Span PN, Foekens JA, Sweep CGJ: Application of a newly developed ELISA for BCAR1 protein for prediction of clinical benefit of tamoxifen therapy in patients with advanced breast cancer. Clin Chem 2004, 50:1445-1447.
• [24]Dorssers LCJ, Grebenchtchikov N, Brinkman A, Look MP, Van Broekhoven SPJ, De Jong D, Peters HA, Portengen H, Meijer-Van Gelder ME, Klijn JGM, et al.: The prognostic value of BCAR1 in patients with primary breast cancer. Clin Cancer Res 2004, 10:6194-6202.
• [25]Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, et al.: Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999, 286:531-537.
• [26]Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, et al.: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000, 403:503-511.
• [27]Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, Pienta KJ, Rubin MA, Chinnaiyan AM: Delineation of prognostic biomarkers in prostate cancer. Nature 2001, 412:822-826.
• [28]van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, et al.: Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415:530-536.
• [29]Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET: Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 2003, 100:10393-10398.
• [30]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 USA 2003, 100:8418-8423.
• [31]Van Agthoven T, Van Agthoven TLA, Portengen H, Foekens JA, Dorssers LCJ: Ectopic expression of epidermal growth factor receptors induces hormone independence in ZR-75-1 human breast cancer cells. Cancer Res 1992, 52:5082-5088.
• [32]Yue H, Eastman PS, Wang BB, Minor J, Doctolero MH, Nuttall RL, Stack R, Becker JW, Montgomery JR, Vainer M, et al.: An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression. Nucleic Acids Res 2001, 29:E41.
• [33]Churchill GA: Fundamentals of experimental design for cDNA microarrays. Nat Genet 2002, 32(Suppl):490-495.
• [34]Van Agthoven T, Van Agthoven TLA, Dekker A, Foekens JA, Dorssers LCJ: Induction of estrogen independence of ZR-75-1 human breast cancer cells by epigenetic alterations. Mol Endocrinol 1994, 8:1474-1483.
• [35]Charpentier AH, Bednarek AK, Daniel RL, Hawkins KA, Laflin KJ, Gaddis S, MacLeod MC, Aldaz CM: Effects of estrogen on global gene expression: identification of novel targets of estrogen action. Cancer Res 2000, 60:5977-5983.
• [36]Soulez M, Parker MG: Identification of novel oestrogen receptor target genes in human ZR75-1 breast cancer cells by expression profiling. J Mol Endocrinol 2001, 27:259-274.
• [37]Lobenhofer EK, Bennett L, Cable PL, Li L, Bushel PR, Afshari CA: Regulation of DNA replication fork genes by 17β-estradiol. Mol Endocrinol 2002, 16:1215-1229.
• [38]Inoue A, Yoshida N, Omoto Y, Oguchi S, Yamori T, Kiyama R, Hayashi S: Development of cDNA microarray for expression profiling of estrogen-responsive genes. J Mol Endocrinol 2002, 29:175-192.
• [39]Hayashi SI, Eguchi H, Tanimoto K, Yoshida T, Omoto Y, Inoue A, Yoshida N, Yamaguchi Y: The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application. Endocr Relat Cancer 2003, 10:193-202.
• [40]Cunliffe HE, Ringner M, Bilke S, Walker RL, Cheung JM, Chen Y, Meltzer PS: The gene expression response of breast cancer to growth regulators: patterns and correlation with tumor expression profiles. Cancer Res 2003, 63:7158-7166.
• [41]Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C, Meltzer PS: Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res 2001, 61:5979-5984.
• [42]Riggins RB, Quilliam LA, Bouton AH: Synergistic promotion of c-Src activation and cell migration by Cas and AND-34/BCAR3. J Biol Chem 2003, 278:28264-28273.
• [43]Lamb J, Ramaswamy S, Ford HL, Contreras B, Martinez RV, Kittrell FS, Zahnow CA, Patterson N, Golub TR, Ewen ME: A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 2003, 114:323-334.
• [44]Eisen MB, Spellman PT, Brown PO, Botstein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998, 95:14863-14868.