A non-DNA binding estrogen receptor isoform: A potential suppressor of breast carcinogenesis.
Item
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Title
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A non-DNA binding estrogen receptor isoform: A potential suppressor of breast carcinogenesis.
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Identifier
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AAI9820529
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identifier
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9820529
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Creator
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Erenburg, Irina.
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Contributor
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Advisers: Liliana Ossowski | Beth Schachter
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Date
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1998
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Oncology | Health Sciences, Obstetrics and Gynecology | Biology, Cell
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Abstract
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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 (ER{dollar}\Delta{dollar}3), 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 {dollar}<{dollar} 0.001). This suggested a link between the relative loss of ER{dollar}\Delta{dollar}3 from normal cells and breast carcinogenesis. To directly test its effect on breast cancer cells, stable clones of MCF-7 cells expressing ectopic ER{dollar}\Delta{dollar}3 protein at levels not exceeding those of physiological ER were generated. In vector transfected controls the ER{dollar}\Delta{dollar}3-mRNA and protein were less than 10% of total ER while in the ER{dollar}\Delta{dollar}3-expressing clones, ER{dollar}\Delta{dollar}3-mRNA and protein represented approximately 50% of the total ER. The presence of ER{dollar}\Delta{dollar}3 in these cells interfered with both estrogen (E2) stimulation of the pS2gene mRNA, (inhibited by more than 90% in all ER{dollar}\Delta{dollar}3-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 ER{dollar}\Delta{dollar}3 revealed a reduction in their malignant potential as well as a reversal of several features that distinguish transformed from normal cells. In presence of 1 {dollar}\times{dollar} 10{dollar}\sp{lcub}-8{rcub}{dollar} M E2, compared to control cells, the ER{dollar}\Delta{dollar}3-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 ER{dollar}\Delta{dollar}3 clones. In addition, our finding of dome and alveolar-like sphere formation, indicate that cells expressing ER{dollar}\Delta{dollar}3 may acquire characteristics of normal mammary epithelial cells in culture. Taken together these findings suggest that ER{dollar}\Delta{dollar}3 may function in normal mammary epithelium to regulate and limit the magnitude of estrogen responses, and that its loss in breast cancer due to an altered splice regulation of ER-mRNA may be a component of breast carcinogenesis.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
