Estradiol Regulates Different Genes in Human Breast Tumor Xenografts Compared With the Identical Cells in Culture

Endocrinology. 2006 Feb;147(2):700-13. doi: 10.1210/en.2005-0617. Epub 2005 Oct 20.

Abstract

In breast cancers, estrogen receptor (ER) levels are highly correlated with response to endocrine therapies. We sought to define mechanisms of estrogen (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: 1) 17beta-estradiol for 8 wk (E); 2) without E for 8 wk (control); 3) E for 7 wk followed by 1 wk of E withdrawal (Ewd); or 4) E for 8 wk plus tamoxifen for the last week. E-regulated genes were defined as those that differed significantly between control and E and/or between E and Ewd or control 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 for the study of 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 with 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Estradiol / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / classification
  • Neoplasm Proteins / drug effects
  • Neoplasm Proteins / metabolism*
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / metabolism*
  • Tamoxifen / pharmacology
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents, Hormonal
  • Neoplasm Proteins
  • Receptors, Estrogen
  • Tamoxifen
  • Estradiol