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Cancer Research 66, 11954, December 15, 2006. doi: 10.1158/0008-5472.CAN-06-1666
© 2006 American Association for Cancer Research

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Endocrinology

Diverse Gene Expression and DNA Methylation Profiles Correlate with Differential Adaptation of Breast Cancer Cells to the Antiestrogens Tamoxifen and Fulvestrant

Meiyun Fan1, Pearlly S. Yan2, Cori Hartman-Frey1, Lei Chen1, Henry Paik1, Samuel L. Oyer1, Jonathan D. Salisbury1, Alfred S.L. Cheng2, Lang Li3, Phillip H. Abbosh1, Tim H-M. Huang2 and Kenneth P. Nephew1,4,5

1 Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana; 2 Division of Human Cancer Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio; 3 Division of Biostatistics, Department of Medicine and 4 Department of Cellular and Integrative Physiology, Indiana University School of Medicine; and 5 Indiana University Cancer Center, Indianapolis, Indiana

Requests for reprints: Kenneth P. Nephew, Medical Sciences, Indiana University School of Medicine, 302 Jordan Hall, 1001 East 3rd Street, Bloomington, IN 47405-4401. Phone: 812-855-9445; Fax: 812-855-4436; E-mail: knephew{at}indiana.edu.

The development of targeted therapies for antiestrogen-resistant breast cancer requires a detailed understanding of its molecular characteristics. To further elucidate the molecular events underlying acquired resistance to the antiestrogens tamoxifen and fulvestrant, we established drug-resistant sublines from a single colony of hormone-dependent breast cancer MCF7 cells. These model systems allowed us to examine the cellular and molecular changes induced by antiestrogens in the context of a uniform clonal background. Global changes in both basal and estrogen-induced gene expression profiles were determined in hormone-sensitive and hormonal-resistant sublines using Affymetrix Human Genome U133 Plus 2.0 Arrays. Changes in DNA methylation were assessed by differential methylation hybridization, a high-throughput promoter CpG island microarray analysis. By comparative studies, we found distinct gene expression and promoter DNA methylation profiles associated with acquired resistance to fulvestrant versus tamoxifen. Fulvestrant resistance was characterized by pronounced up-regulation of multiple growth-stimulatory pathways, resulting in estrogen receptor {alpha} (ER{alpha})–independent, autocrine-regulated proliferation. Conversely, acquired resistance to tamoxifen correlated with maintenance of the ER{alpha}-positive phenotype, although receptor-mediated gene regulation was altered. Activation of growth-promoting genes, due to promoter hypomethylation, was more frequently observed in antiestrogen-resistant cells compared with gene inactivation by promoter hypermethylation, revealing an unexpected insight into the molecular changes associated with endocrine resistance. In summary, this study provides an in-depth understanding of the molecular changes specific to acquired resistance to clinically important antiestrogens. Such knowledge of resistance-associated mechanisms could allow for identification of therapy targets and strategies for resensitization to these well-established antihormonal agents. (Cancer Res 2006; 66(24): 11954–66)




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