Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

Teresa Rose-Hellekant, M. D. Schroeder, J. L. Brockman, Olga Zhdankin, R. Bolstad, K. S. Chen, M. N. Gould, L. A. Schuler, E. P. Sandgren

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

We characterized the novel NRL-transforming growth factor alpha (NRL-TGFα) transgenic mouse model in which growth factor - steroid receptor interactions were explored. The NRL promoter directs transgene expression to mammary ductal and alveolar cells and is nonresponsive to estrogen manipulations in vitro and in vivo. NRL-TGFα mice acquire proliferative hyperplasias as well as cystic and solid tumors. Quantitative transcript analysis revealed a progressive decrease in estrogen receptor alpha (ER) and progesterone receptor (PR) mRNA levels with tumorigenesis. However, ER protein was evident in all lesion types and in surrounding stromal cells using immunohistochemistry. PR protein was identified in normal epithelial cells and in very few cells of small epithelial hyperplasias, but never in stromal or tumor cells. Prophylactic ovariectomy significantly delayed tumor development and decreased incidence. Finally, while heterozygous (+/-) p53 mice did not acquire mammary lesions, p53+/- mice carrying the NRL-TGFα transgene developed ER negative/PR negative undifferentiated carcinomas. These data demonstrate that unregulated TGFα expression in the mammary gland leads to oncogenesis that is dependent on ovarian steroids early in tumorigenesis. Resulting tumors resemble a clinical phenotype of ER+/PR-, and when combined with a heterozygous p53 genotype, ER-/PR-.

Original languageEnglish (US)
Pages (from-to)5238-5246
Number of pages9
JournalOncogene
Volume26
Issue number36
DOIs
StatePublished - Aug 9 2007

Keywords

  • Breast cancer
  • Estrogen receptor
  • Mammary cancer
  • Progesterone receptor
  • TGFa
  • Transgenic mice

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