H-ras Dependent Estrogenic Effects of Epidermal Growth Factor in the Estrogen-Independent Breast Cancer Cell Line MDA-MB-231

Breast Cancer Res Treat. 2003 Jul;80(2):155-62. doi: 10.1023/A:1024502107690.

Abstract

A crosstalk between cellular estrogen response and receptor tyrosine kinase signaling has been shown in a variety of estrogen receptor (ER)-positive cell lines. We intended to examine the presence of estrogenic growth factor effects in an ER alpha-negative breast cancer cell line. By means of reporter gene assays, we investigated the activation of estrogen response elements (EREs) by epidermal growth factor (EGF) in the estrogen-unresponsive cell line MDA-MB-231. Our results demonstrate the H-ras-dependent activation of EREs after EGF treatment in this estrogen-unresponsive cell line, an effect which was not observed in the ERalpha/beta-positive breast cancer cell line MCF-7. In MDA-MB-231 cells, the transcriptional activity of an ERE-containing promotor was enhanced dose dependently by all tested EGF concentrations. This effect could be blocked by co-treatment with the epidermal growth factor receptor (EGFR) inhibitors AG1478 and ZD1839, as well as by co-transfection with a vector coding for a dominant negative H-ras mutant, but not by co-treatment with the pure antiestrogen ICI182,780. Furthermore, expression of constitutively active H-ras was shown to be sufficient to activate EREs in MDA-MB-231 cells. Our results suggest alternative utilization of ERE-mediated gene regulation in an estradiol-unresponsive breast cancer cell line in response to an EGF stimulus. This mechanism was shown to be dependent on EGFR and H-ras activity, but independent of the presence of functional ERalpha.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Division
  • Cell Line, Tumor
  • Epidermal Growth Factor / pharmacology*
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Female
  • Fulvestrant
  • Gene Expression Regulation, Neoplastic
  • Genes, ras
  • Humans
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism*
  • Neoplasms, Hormone-Dependent / pathology
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / metabolism*
  • Response Elements / drug effects

Substances

  • Receptors, Estrogen
  • Fulvestrant
  • Estradiol
  • Epidermal Growth Factor