Loss of an estrogen receptor isoform (ER alpha delta 3) in breast cancer and the consequences of its reexpression: interference with estrogen-stimulated properties of malignant transformation

Mol Endocrinol. 1997 Dec;11(13):2004-15. doi: 10.1210/mend.11.13.0031.


Comparison of mRNA ratios of a non-DNA-binding estrogen receptor (ER(alpha)) isoform, missing exon 3 (ER(alpha)delta3), to the full-length ER(alpha), in normal breast epithelium to that in primary breast cancers and breast cancer cell lines revealed a 30-fold reduction of this ratio in cancer cells (P < 0.0001). To test what functions may have been affected by the loss of ER(alpha)delta3, stable clones of MCF-7 cells expressing ectopic ER(alpha)delta3 protein, at the range of physiological ER(alpha), were generated. In vector-transfected controls the ER(alpha)delta3-mRNA and protein were less than 10% while in the ER(alpha)delta3-expressing clones, ER(alpha)delta3-mRNA and protein ranged from 36-76% of the total ER(alpha). Estrogen (E2) stimulated the expression of pS2-mRNA in pMV7 vector control cells, but the stimulation was reduced by up to 93% in ER(alpha)delta3-expressing clones. In addition, several properties associated with the transformed phenotype were also strongly affected when ER(alpha)delta3 protein was reexpressed. Compared with vector-transfected control cells, the saturation density of the ER(alpha)delta3-expressing clones was reduced by 50-68%, while their exponential growth rate was only slightly (14.5 +/- 5%) lower. The in vivo invasiveness of the ER(alpha)delta3-expressing cells was significantly reduced (P = 0.007) by up to 79%. E2 stimulated anchorage-independent growth of the pMV7 vector control cells, but reduced it to below baseline levels in ER(alpha)delta3 clones. The reduction of the pS2 response to E2 in the ER(alpha)delta3-expressing clones and the E2 block of anchorage-independent growth to below baseline were more pronounced than expected from the dominant negative function of ER(alpha)delta3. These observations suggest that E2 may activate an additional ER(alpha)delta3-dependent inhibitory pathway. The drastic reduction of ER(alpha)delta3 to ER(alpha) ratio in breast cancer, and the fact that when present in breast cancer cells this isoform leads to a suppression, rather than enhancement, of the transformed phenotype by E2 suggests that the regulation of ER(alpha)-mRNA splicing may need to be altered for the breast carcinogenesis to proceed.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Breast / cytology
  • Breast / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Count / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Estrogen Receptor alpha
  • Estrogens / physiology*
  • Female
  • Gene Deletion*
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Isomerism
  • Middle Aged
  • Phenotype
  • Protein Binding / drug effects
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Receptors, Estrogen / genetics*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Transfection
  • Transgenes
  • Tumor Cells, Cultured


  • Estrogen Receptor alpha
  • Estrogens
  • RNA, Messenger
  • Receptors, Estrogen
  • Recombinant Proteins