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B Peng
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B Lu
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E Leygue
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LC Murphy
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Estrogen receptors (ERalpha and ERbeta) are clearly multifaceted in terms of structure and function. Several relatively abundant ERbeta isoforms have been identified, which can be differentially expressed in various tIssues. In order to provide insight into the possible role of the ERbeta family in breast tIssue a study of the putative functions of the human (h) ERbeta1, hERbeta2 and hERbeta5 isoforms was undertaken. Only hERbeta1 was found to bind ligand, which induced conformational changes as determined by protease digestion assays. All ERbeta isoforms could bind to and bend DNA although the relative efficiency with which they bound DNA differed with hERalpha>hERbeta1>hERbeta2>>hERbeta5. All ERbeta isoforms inhibited ERalpha transcriptional activity on an estrogen-response element (ERE)-reporter gene. The relative activities were hERbeta1>hERbeta2>hERbeta5; however, only hERbeta1 had transcriptional activity of its own. Both LY117018-hERalpha and LY117018-hERbeta1 complexes alone could activate transcription on a TGF-beta3-CAT gene. Although hERbeta2 and hERbeta5 had no activity alone, they inhibited ERalpha but not hERbeta1 transcriptional activity of transforming growth factor (TGF)-beta3-CAT. In marked contrast to activity on an ERE-CAT reporter gene, hERbeta1 did not modulate ERalpha transcriptional activity on a TGF-beta3-CAT reporter gene. These data support promoter-specific differential activities of hERbeta isoforms with respect to models of ERalpha regulated gene expression, and suggest that they may have a role in differentially modulating estrogen action.

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L C Murphy Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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B Peng Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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A Lewis Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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J R Davie Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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E Leygue Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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A Kemp Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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K Ung Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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M Vendetti Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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R Shiu Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, Canada
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

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To investigate the effect of altered oestrogen receptor (ER)α and ERβ expression on oestrogen and anti-oestrogen action in breast cancer, we have stably expressed an inducible ERβ1 in MCF7 breast cancer cells. Stably expressing clones were isolated and over-expression of ERβ1 correlated with increased levels of specific radiolabelled oestradiol (E2) binding. Increased ERβ1 did not affect endogenous levels of ERα but increased progesterone receptor (PR) levels. Over-expression of ERβ1 reduced growth responses to E2 in contrast to little if any effect of over-expression of ERα. In oestrogen-replete conditions, over-expression of ERβ1 but not ERα reduced proliferation. Over-expression of ERβ1 did not result in anti-oestrogen resistance but was associated with increased sensitivity to 4-hydroxytamoxifen. Our results suggested that over-expression of ERβ1 in the presence of an endogenously expressed ERα was associated with tamoxifen sensitivity but may negatively modulate ERα-mediated growth. However, not all ERα activities were inhibited since endogenous PR expression was increased by both ERα and ERβ1 over-expression. These data paralleled those seen in some in vivo studies showing a relationship between PR and ERβ expression as well as ERβ expression and tamoxifen sensitivity of ER-positive breast cancer patients. These models are relevant and will be useful for dissecting the role of ERβ1 expression in ER-positive breast cancer.

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