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Loss of an Estrogen Receptor Isoform (ER3) in Breast Cancer and the Consequences of Its Reexpression: Interference with Estrogen-Stimulated Properties of Malignant Transformation

Department of Cell Biology (I.E., B.S., L.O.) Rochelle Belfer Chemotherapy Foundation Laboratory (I.E., R.M.L., L.O) Department of Medicine Department of Obstetrics and Gynecology (B.S.) Mount Sinai School of Medicine New York, New York 10029

Comparison of mRNA ratios of a non-DNA-binding estrogen receptor (ER) isoform, missing exon 3 (ER3), to the full-length ER, 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 ER3, stable clones of MCF-7 cells expressing ectopic ER3 protein, at the range of physiological ER, were generated. In vector-transfected controls the ER3-mRNA and protein were less than 10% while in the ER3-expressing clones, ER3-mRNA and protein ranged from 36–76% of the total ER. Estrogen (E₂) stimulated the expression of pS2-mRNA in pMV7 vector control cells, but the stimulation was reduced by up to 93% in ER3-expressing clones. In addition, several properties associated with the transformed phenotype were also strongly affected when ER3 protein was reexpressed. Compared with vector-transfected control cells, the saturation density of the ER3-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 ER3-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 ER3 clones. The reduction of the pS2 response to E₂ in the ER3-expressing clones and the E₂ block of anchorage-independent growth to below baseline were more pronounced than expected from the dominant negative function of ER3. These observations suggest that E₂ may activate an additional ER3-dependent inhibitory pathway. The drastic reduction of ER3 to ER 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-mRNA splicing may need to be altered for the breast carcinogenesis to proceed.

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