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Submitted on May 23, 2005
Accepted on October 12, 2005
Department of Medicine, Division of Endocrinology, and Department of Pathology, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado; Breast Center, Baylor College of Medicine, Houston, Texas
* To whom correspondence should be addressed. E-mail: djuana.harvell{at}uchsc.edu.
In breast cancers, estrogen receptor (ER) levels are highly correlated with response to endocrine therapies. We sought to define mechanisms of estradiol (E) signaling in a solid breast tumor model using gene expression profiling. ER+ T47D-Y human breast cancer cells were grown as xenografts in ovariectomized nude mice under four conditions: i. E for 8 weeks (E); ii. without E for 8 weeks (controls, C); iii. E for 7 weeks followed by 1 week of E withdrawal (Ewd), or iv. E for 8 weeks with Tamoxifen for the last week (E+Tam). E-regulated genes were defined as those that differed significantly between C and E, and/or between E and Ewd. These protocols generated 188 in vivo E-regulated genes that showed two major patterns of regulation. Approximately 46% returned to basal states after Ewd (Class I genes); 53% did not (Class II genes). In addition, more than 70% of Class II regulated genes also failed to reverse in response to Tamoxifen. These genes may be interesting to study hormone resistance issues. A subset of in vivo E-regulated genes appears on lists of clinical "ER discriminator" genes. These may be useful therapeutic targets or markers of E activity. Comparison of in vivo E-regulated genes to those regulated in identical cells in vitro after 6 and 24 h of E treatment demonstrate only 11% overlap. This indicates the extent to which gene expression profiles are uniquely dependent on hormone treatment times and the cellular microenvironment.
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