This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gu, Z. Articles by Clarke, R. Search for Related Content PubMed PubMed Citation Articles by Gu, Z. Articles by Clarke, R.

Association of Interferon Regulatory Factor-1, Nucleophosmin, Nuclear Factor-B, and Cyclic AMP Response Element Binding with Acquired Resistance to Faslodex (ICI 182,780)¹

Vincent T. Lombardi Cancer Center and Department of Oncology, Georgetown University School of Medicine, Washington, DC 20007 [Z. G., R. Y. L., T. C. S., K. B. B., J. N. W., A. L., Y. Z., N. D., F. L., R. C.]; Department of Electrical Engineering and Computer Science, The Catholic University of America, Washington, DC 20064 [J. L., Y. W.]; and Finsen Laboratory, Copenhagen, Denmark [N. B.]

To identify genes associated with survival from antiestrogens, both serial analysis of geneexpression and gene expression microarrays were used to explore the transcriptomes of antiestrogen-responsive (MCF7/LCC1) and -resistant variants(MCF7/LCC9) of the MCF-7 human breast cancer cell line. Structure of the gene microarray expression data was visualized at the top level using a novel algorithm that derives the first three principal components,fitted to the antiestrogen-resistant and -responsive gene expression data, from Fisher’s information matrix. The differential regulation of several candidate genes was confirmed. Functional studies of the basal expression and endocrine regulation of transcriptional activation of implicated transcription factors were studied using promoter-reporter assays.

The putative tumor suppressor interferon regulatory factor-1 is down-regulated in resistant cells, whereas its nucleolar phosphoprotein inhibitor nucleophosmin is up-regulated. Resistant cells also up-regulate the transcriptional activation of cyclic AMP response element (CRE) binding and nuclear factor B (NFB) while down-regulating epidermal growth factor receptor protein expression. Inhibition of NFB activity by ICI 182,780 is lost in resistant cells, but CRE activity is not regulated by ICI 182,780 in either responsive or resistant cells. Parthenolide, a potent and specific inhibitor of NFB, inhibits the anchorage-dependent proliferation of antiestrogen-resistant but not antiestrogen-responsive cells. This observation implies a greater reliance on their increased NFB signaling for proliferation in cells that have survived prolonged exposure to ICI 182,780.

These data from serial analysis of gene expression and gene microarray studies implicate changes in a novel signaling pathway, involving interferon regulatory factor-1, nucleophosmin, NFB, and CRE binding in cell survival after antiestrogen exposure. Cells can up-regulate some estrogen-responsive genes while concurrently losing the ability of antiestrogens to regulate their expression. Signaling pathways that are not regulated by estrogens also can be up-regulated. Thus, some breast cancer cells may survive antiestrogen treatment by bypassing specific growth inhibitory signals induced by antagonist-occupied estrogen receptors.

This article has been cited by other articles:

				B. P. Gomez, R. B. Riggins, A. N. Shajahan, U. Klimach, A. Wang, A. C. Crawford, Y. Zhu, A. Zwart, M. Wang, and R. Clarke Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines FASEB J, December 1, 2007; 21(14): 4013 - 4027. [Abstract] [Full Text] [PDF]

				M. Fan, P. S. Yan, C. Hartman-Frey, L. Chen, H. Paik, S. L. Oyer, J. D. Salisbury, A. S.L. Cheng, L. Li, P. H. Abbosh, et al. Diverse Gene Expression and DNA Methylation Profiles Correlate with Differential Adaptation of Breast Cancer Cells to the Antiestrogens Tamoxifen and Fulvestrant Cancer Res., December 15, 2006; 66(24): 11954 - 11966. [Abstract] [Full Text] [PDF]

				A. J Lengi, R. A Phillips, E. Karpuzoglu, and S. A. Ahmed 17{beta}-Estradiol downregulates interferon regulatory factor-1 in murine splenocytes J. Mol. Endocrinol., December 1, 2006; 37(3): 421 - 432. [Abstract] [Full Text] [PDF]

				S. K. Rayala, J. Mascarenhas, R. K. Vadlamudi, and R. Kumar Altered localization of a coactivator sensitizes breast cancer cells to tumor necrosis factor-induced apoptosis. Mol. Cancer Ther., February 1, 2006; 5(2): 230 - 237. [Abstract] [Full Text] [PDF]

				K-M Rau, H-Y Kang, T-L Cha, S A Miller, and M-C Hung The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers Endocr. Relat. Cancer, September 1, 2005; 12(3): 511 - 532. [Abstract] [Full Text] [PDF]

				K. B. Bouker, T. C. Skaar, R. B. Riggins, D. S. Harburger, D. R. Fernandez, A. Zwart, A. Wang, and R. Clarke Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis Carcinogenesis, September 1, 2005; 26(9): 1527 - 1535. [Abstract] [Full Text] [PDF]

				S. Mukherjee and S. E. Conrad c-Myc Suppresses p21WAF1/CIP1 Expression during Estrogen Signaling and Antiestrogen Resistance in Human Breast Cancer Cells J. Biol. Chem., May 6, 2005; 280(18): 17617 - 17625. [Abstract] [Full Text] [PDF]

				R. B. Riggins, A. Zwart, R. Nehra, and R. Clarke The nuclear factor {kappa}B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells Mol. Cancer Ther., January 1, 2005; 4(1): 33 - 41. [Abstract] [Full Text] [PDF]

				A. Mitchell, C. R. Dass, L.-Q. Sun, and L. M. Khachigian Inhibition of human breast carcinoma proliferation, migration, chemoinvasion and solid tumour growth by DNAzymes targeting the zinc finger transcription factor EGR-1 Nucleic Acids Res., June 4, 2004; 32(10): 3065 - 3069. [Abstract] [Full Text] [PDF]

				K. B. Bouker, T. C. Skaar, D. R. Fernandez, K. A. O'Brien, R. B. Riggins, D. Cao, and R. Clarke Interferon Regulatory Factor-1 Mediates the Proapoptotic but Not Cell Cycle Arrest Effects of the Steroidal Antiestrogen ICI 182,780 (Faslodex, Fulvestrant) Cancer Res., June 1, 2004; 64(11): 4030 - 4039. [Abstract] [Full Text] [PDF]

				H. Liu, E.-S. Lee, C. Gajdos, S. T. Pearce, B. Chen, C. Osipo, J. Loweth, K. McKian, A. De Los Reyes, L. Wing, et al. Apoptotic Action of 17{beta}-Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo J Natl Cancer Inst, November 5, 2003; 95(21): 1586 - 1597. [Abstract] [Full Text] [PDF]