Loss of an Estrogen Receptor Isoform (ER 3) in Breast Cancer and the Consequences of Its Reexpression: Interference with Estrogen-Stimulated Properties of Malignant Transformation

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Abstract
Comparison of mRNA ratios of a non-DNA-binding estrogen receptor (ERa) isoform, missing exon 3 (ERaD3), to the full-length ERa, in normal breast epithelium to that in primary breast cancers and breast cancer cell lines revealed a 30-fold reduc- tion of this ratio in cancer cells (P < 0.0001). To test what functions may have been affected by the loss of ERaD3, stable clones of MCF-7 cells expressing ectopic ERaD3 protein, at the range of physiologi- cal ERa, were generated. In vector-transfected controls the ERaD3-mRNA and protein were less than 10% while in the ERaD3-expressing clones, ERaD3-mRNA and protein ranged from 36-76% of the total ERa. Estrogen (E2) stimulated the expres- sion of pS2-mRNA in pMV7 vector control cells, but the stimulation was reduced by up to 93% in ERaD3-expressing clones. In addition, several properties associated with the transformed pheno- type were also strongly affected when ERaD3 pro- tein was reexpressed. Compared with vector- transfected control cells, the saturation density of the ERaD3-expressing clones was reduced by 50- 68%, while their exponential growth rate was only slightly (14.5 6 5%) lower. The in vivo invasiveness of the ERaD3-expressing cells was significantly re- duced (P 5 0.007) by up to 79%. E2 stimulated anchorage-independent growth of the pMV7 vec- tor control cells, but reduced it to below baseline levels in ERaD3 clones. The reduction of the pS2 response to E2 in the ERaD3-expressing clones and the E2 block of anchorage-independent growth to below baseline were more pronounced than expected from the dominant negative function of ERaD3. These observations suggest that E2 may activate an additional ERaD3-dependent inhibitory pathway. The drastic reduction of ERaD 3t o ER a 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 ERa-mRNA splicing may need to be altered for the breast carcinogenesis to proceed. (Molecular Endocrinology 11: 2004-2015, 1997)

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