Characterization and Consequences of Estrogen Receptor Exon Five Deletion.
Abstract
Estrogen, a key regulator of normal breast growth and differentiation, has been shown to promote both cancer cell proliferation and invasion. This steroid hormone mediates its effect via the estrogen receptor (ER), a member of the nuclear receptor family of transcription factors. A comparison of mRNA ratios of a non-DNA binding estrogen receptor isoform, missing exon 3 (ERdelta3), to the full length ER in breast cancer, cancer cell lines and normal mammary epithelial cells and fibroblasts, revealed a 30 fold reduction of this ratio in cancer cells (p < 0.001). This suggested a link between the relative loss of ERdelta3 from normal cells and breast carcinogenesis. To directly test its effect on breast cancer cells, stable clones of MCF-7 cells expressing ectopic ERdelta3 protein at levels not exceeding those of physiological ER were generated. In vector transfected controls the ERdelta3-mRNA and protein were less than 10% of total ER while in the ERdelta3-expressing clones, ERdelta3-mRNA and protein represented approximately 50% of the total ER. The presence of ERdelta3 in these cells interfered with both estrogen (E2) stimulation of the pS2 gene mRNA, (inhibited by more than 90% in all ERdelta3-MCF-7 clones as compared with the pMV7 vector transfected control cells), and estrogen mediated down-regulation of its own receptor. Furthermore, analyses of the cells expressing ERdelta3 revealed a reduction in their malignant potential as well as a reversal of several features that distinguish transformed from normal cells. In presence of 1x10(exp -8) M E2, compared to control cells, the ERdelta3-expressing cells were density arrested at 50%, and their invasiveness in vivo was reduced by up to 79%. As expected, estrogen stimulated anchorage independent growth of both the control pMV7 vector transfected cells and the parental MCF-7 cells, but reduced it to below baseline levels in ERdelta3 clones.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 1998
- Accession Number
- ADA371298
Entities
People
- Irina Erenburg
Organizations
- Icahn School of Medicine at Mount Sinai