Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis
Impaired histone acetylation was recognized to be involved in carcinogenesis. Furthermore, histone deacetylase (HDAC) inhibitors induce differentiation of breast cancer cells and inhibit tumour growth. These results prompted us to study HDAC-1 and -3 expression in breast tumours to establish their potential therapeutic and prognostic significance.
HDAC-1 und HDAC-3 protein expression was analyzed immunohistochemically on a tissue microarray (TMA) containing 600 core biopsies from 200 patients. HDAC-1 and -3 expression was correlated to steroid hormone receptor-, Her2/neu- and proliferation status of tumours as well as to overall and disease free survival.
Moderate or strong nuclear immunoreactivity for HDAC-1 was observed in 39.8% and for HDAC-3 in 43.9% of breast carcinomas. HDAC-1 and -3 expression correlated significantly with oestrogen and progesterone receptor expression (both p< 0.001). HDAC-1 expression predicted significantly better disease free survival (DFS: p=0.044), in particular, in patients with small tumours of all differentiation types (DFS: p=0.016). Multivariate analysis demonstrated that HDAC-1 is an independent prognostic marker.
Our data suggest that evaluation of HDAC-1 protein expression enables a more precise assessment of the prognosis of breast cancer patients. Thus, HDAC-1 expression analysis might be clinically useful to facilitate an individual, risk-directed, adjuvant systemic therapy in breast cancer patients.
Keywordsbreast cancer cell differentiation histone deacetylases prognostic marker survival
Momparler, RL 2003Cancer epigeneticsOncogene2264796483PubMedGoogle Scholar Thiagalingam, S, Cheng, KH, Lee, H, Mineva, N, Thiagalingam, A, Ponte, JF 2003Histone deacetylases: unique players in shaping the epigenetic histone codeAnn NY Acad Sci98384100CrossRefPubMedGoogle Scholar Yan, L, Yang, X, Davidson, NE 2001Role of DNA methylation and histone acetylation in steroid receptor expression in breast cancerJ Mammary Gland Biol Neoplasia6183192PubMedGoogle Scholar Cress, WD, Seto, E 2000Histone deacetylases, transcriptional control, and cancerJ Cell Physiol184116PubMedGoogle Scholar Lagger, G, Doetzlhofer, A, Schuettengruber, B, Haidweg, E, Simboeck, E, Tischler, J, Chiocca, S, Suske, G, Rotheneder, H, Wintersberger, E, Seiser, C 2003The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 geneMol Cell Biol2326692679PubMedGoogle Scholar Lagger, G, O’Carroll, D, Rembold, M, Khier, H, Schuettengruber, B, Hauser, C, Brunmeir, R, Jenuwein, T, Seiser, C 2002Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repressionEMBO J2126722681PubMedGoogle Scholar Davis, T, Kennedy, C, Chiew, YE, Clarke, CL, Fazio, A 2000Histone deacetylase inhibitors decrease proliferation and modulate cell cycle gene expression in normal mammary epithelial cellsClin Cancer Res643344342PubMedGoogle Scholar Keen, JC, Yan, L, Mack, KM, Pettit, C, Smith, D, Sharma, D, Davidson, NE 2003A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza-2′-deoxycytidineBreast Cancer Res Treat81177186PubMedGoogle Scholar Jang, ER, Lim, SJ, Lee, ES, Jeong, G, Kim, TY, Bang, YJ, Lee, JS 2004The histone deacetylase inhibitor trichostatin A sensitizes oestrogen receptor α-negative breast cancer cells to tamoxifenOncogene2317241736PubMedGoogle Scholar Fuino, L, Bali, P, Wittmann, S, Donapaty, S, Guo, F, Yamaguchi, H, Wang, HG, Atadja, P, Bhalla, K 2003Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone BMol Cancer Ther2971984PubMedGoogle Scholar Vigushin, DM, Ali, S, Pace, PE, Mirsaidi, N, Ito, K, Adcock, I, Coombes, RC 2001Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivoClin Cancer Res7971976PubMedGoogle Scholar Kuperwasser, C, Pinkas, J, Hurlbut, GB, Naber, SP, Jerry, DJ 2000Cytoplasmic sequestration and functional repression of p53 in the mammary epithelium is reversed by hormonal treatmentCancer Res6027232729PubMedGoogle Scholar Zhang, HS, Dean, DC 2001Rb-mediated chromatin structure regulation and transcriptional repressionOncogene2031343138PubMedGoogle Scholar Glaser, KB, Li, J, Staver, MJ, Wie, RQ, Albert, DH, Davidsen, SK 2003Role of class I and class II histone deacetylases in carcinoma cells using siRNABiochem Biophy Res Commun310529536Google Scholar Guenther, MG, Barak, O, Lazar, MA 2001The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3Mol Cell Biol2160916101PubMedGoogle Scholar Yarden, RI, Brody, LC 1999BRCA1 interacts with components of the histone deacetylase complexProc Natl Acad Sci USA9649834988PubMedGoogle Scholar Kononen, J, Bubendorf, L, Kallioniemi, A, Barlund, M, Schraml, P, Leighton, S, Torhorst, J, Milhatsch, MJ, Sauter, G, Kallioniemi, OP 1998Tissue microarrays for high-throughput molecular profiling of tumor specimensNat Med4844847PubMedGoogle Scholar Wülfing, P, Diallo, R, Müller, C, Wülfing, C, Poremba, C, Heinecke, A, Rody, A, Greb, RR, Böcker, W, Kiesel, L 2003Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysisJ Cancer Res Clin Oncol129375382PubMedGoogle Scholar Reiner, A, Neumeister, B, Spona, J, Reiner, G, Schemper, M, Jakesz, R 1990Immunocytochemical localization of estrogen and progesterone receptor and prognosis in human primary breast cancerCancer Res5010571061Google Scholar Poremba, C, Boecker, W, Willenbring, H, Schafer, KL, Otterbach, F, Burger, H, Diallo, R, Dockhorn-Dworniczak, B 1998Telomerase activity in human proliferative breast lesionsInt J Oncol12641648PubMedGoogle Scholar
Altman DG: Chi square test for trend. In: Practical Statistics for Medical Research. Chapman & Hall, London, 1995, pp 261–265.Google Scholar
Kouraklis, G, Theocharis, S 2002Histone deacetylase inhibitors and anticancer therapyCurr Med Chem Anti-Canc Agents2477484Google Scholar Goldhirsch, A, Glick, JH, Gelber, RD, Coates, AS, Senn, HJ 2001Meeting highlights: international consensus panel on the treatment of primary breast cancerJ Clin Oncol1938173827PubMedGoogle Scholar Hoos, A, Urist, MJ, Stojadinovic, A, Mastorides, S, Dudas, ME, Leung, DHJ, Kuo, D, Brennan, MF, Lewis, JL, Cordon-Cardo, C 2001Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumoursAm J Pathol15812451251PubMedGoogle Scholar van’t Veer, LJ, Dai, H, Vijver, MJ, He, YD, Hart, AAM, Mao, M, Peterse, HL, Kooy, K, Marton, MJ, Witteveen, AT, Schreiber, GJ, Kerkhoven, RM, Roberts, C, Linsley, PS, Bernards, R, Friend, SH 2002Gene expression profiling predicts clinical outcome of breast cancerNature415530536CrossRefPubMedGoogle Scholar Santini, D, Ceccarelli, C, Taffurelli, M, Pileri, S, Marrano, D 1996Differentiation pathways in primary invasive breast carcinoma as suggested by intermediate filament and biopathological marker expressionJ Pathol179386391PubMedGoogle Scholar Clarke, RB 2003Steroid receptors and proliferation in human breastSteroids68789794PubMedGoogle Scholar Kawai, H, Li, H, Avraham, S, Jiang, S, Avraham, HK 2003Over expression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of oestrogen receptor alphaInt J Cancer107353358PubMedGoogle Scholar