Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors.
The estrogen-receptor-related receptors (ERRs) alpha, beta, and gamma are orphan nuclear hormone receptors that share significant homology with the estrogen receptors (ERs) but are not activated by natural estrogens. In contrast, the ERRs display constitutive transcriptional activity in the absence of exogenously added ligand. However, the ERRs bind to the estrogen response element and to the extended half-sites of which a subset can also be recognized by ERalpha, suggesting that ERRs and ERs may control overlapping regulatory pathways. To test this hypothesis, we explored the possibility that ERRs could regulate the expression of the estrogen-inducible pS2 gene, a human breast cancer prognostic marker. Transfection studies show that all of the ERR isoforms can activate the pS2 promoter in a variety of cell types, including breast cancer cell lines. Surprisingly, sequence analysis combined with mutational studies revealed that, in addition to the well-characterized estrogen response element, the presence of a functional extended half-site within the pS2 promoter is also required for complete response to both ER and ERR pathways. We show that ERR transcriptional activity on the pS2 promoter is considerably enhanced in the presence of all three members of the steroid receptor coactivator family but is completely abolished on treatment with the synthetic estrogen diethylstilbestrol, a recently described inhibitor of ERR function. Finally, we demonstrate that ERRalpha is the major isoform expressed in human breast cancer cell lines and that diethylstilbestrol can inhibit the growth of both ER-positive and -negative cell lines. Taken together, these results demonstrate that estrogen-inducible genes such as pS2 can be ERR targets and suggest that pharmacological modulation of ERRalpha activity may have therapeutic value in the treatment of breast cancer.
Lu
D
D
Molecular Oncology Group, McGill University Health Centre, Montréal, Québec, H3A 1A1 Canada.
Kiriyama
Y
Y
Lee
K Y
KY
Giguère
V
V
D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D004054:Diethylstilbestrol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011506:Proteins / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D000097983:ERRalpha Estrogen-Related Receptor
D014408:Biomarkers, Tumor; D004054:Diethylstilbestrol; D006131:Growth Inhibitors; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D000097983:ERRalpha Estrogen-Related Receptor; C490918:ESRRB protein, human; C490917:ESRRG protein, human; C051838:TFF1 protein, human; C107914:estrogen receptor-related receptor beta; C538859:NCOA1 protein, human