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Characterization and Consequences of Estrogen Receptor Exon Five Deletion.

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Final rept. 1 Sep 94-31 Aug 98

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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 1x10exp -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.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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