Genomic Structure of the Promoters of the Human Estrogen Receptor-α Gene Demonstrate Changes in Chromatin Structure Induced by AP2γ

Abstract

Expression of human estrogen receptor-α (ERα) involves the activity from several promoters that give rise to alternate untranslated 5′ exons. However, the genomic locations of the alternate 5′ exons have not been reported previously. We have developed a contig map of the human ERα gene that includes all of the known alternate 5′ exons. By using S1 nuclease and 5′- rapid amplification of cDNA ends, the cap sites for the alternate ERα transcripts E and H were identified. DNase I-hypersensitive sites specific to ERα-positive cells were associated with each of the cap sites. A DNase I-hypersensitive site, HS1, was localized to binding sites for AP2 in the untranslated region of exon 1 and was invariably present in the chromatin structure of ERα-positive cells. Overexpression of AP2γ in human mammary epithelial cells generated the HS1-hypersensitive site. The ERα promoter was induced by AP2γ in mammary epithelial cells, and trans-activation was dependent upon the region of the promoter containing the HS1 site. These results demonstrate that AP2γ trans-activates the ERα gene in hormone-responsive tumors by inducing changes in the chromatin structure of the ERα promoter. These data are further evidence for a critical role for AP2 in the oncogenesis of hormone-responsive breast cancers. Expression of human estrogen receptor-α (ERα) involves the activity from several promoters that give rise to alternate untranslated 5′ exons. However, the genomic locations of the alternate 5′ exons have not been reported previously. We have developed a contig map of the human ERα gene that includes all of the known alternate 5′ exons. By using S1 nuclease and 5′- rapid amplification of cDNA ends, the cap sites for the alternate ERα transcripts E and H were identified. DNase I-hypersensitive sites specific to ERα-positive cells were associated with each of the cap sites. A DNase I-hypersensitive site, HS1, was localized to binding sites for AP2 in the untranslated region of exon 1 and was invariably present in the chromatin structure of ERα-positive cells. Overexpression of AP2γ in human mammary epithelial cells generated the HS1-hypersensitive site. The ERα promoter was induced by AP2γ in mammary epithelial cells, and trans-activation was dependent upon the region of the promoter containing the HS1 site. These results demonstrate that AP2γ trans-activates the ERα gene in hormone-responsive tumors by inducing changes in the chromatin structure of the ERα promoter. These data are further evidence for a critical role for AP2 in the oncogenesis of hormone-responsive breast cancers. estrogen receptor α kilobase pair kilobase rapid amplification of cDNA ends human mammary epithelial cells minimal essential media fetal calf serum polymerase chain reaction phosphate-buffered saline glutathioneS-transferase cytomegalovirus multiplicity of infection base pair green fluorescent protein There are at least two nuclear receptors for estrogen receptor, ERα1 (1Green S. Walter P. Kumar V. Krust A. Bornert J.M. Argos P. Chambon P. Nature. 1986; 320: 134-139Crossref PubMed Scopus (1938) Google Scholar, 2Greene G.L. Gilna P. Waterfield M. Baker A. Hort Y. Shine J. Science. 1986; 231: 1150-1154Crossref PubMed Scopus (1047) Google Scholar) and ERβ (3Mosselman S. Polman J. Dijkema R. FEBS Lett. 1996; 392: 49-53Crossref PubMed Scopus (2032) Google Scholar). Most breast cancers that occur in post-menopausal women overexpress ERα (4Jordan V.C. Wolf M.F. Mirecki D.M. Whitford DA Weshons W.V. CRC Crit. Rev. Clin. Lab. Sci. 1988; 26: 97-152Crossref Scopus (54) Google Scholar). Patients with breast cancers that express ERα are more likely to respond to hormonal therapy (4Jordan V.C. Wolf M.F. Mirecki D.M. Whitford DA Weshons W.V. CRC Crit. Rev. Clin. Lab. Sci. 1988; 26: 97-152Crossref Scopus (54) Google Scholar, 5Bradbeer J.W. Kyngdon J. Clin. Oncol. 1983; 9: 31-34PubMed Google Scholar) and have an improved prognosis compared with patients with ERα-negative tumors (4Jordan V.C. Wolf M.F. Mirecki D.M. Whitford DA Weshons W.V. CRC Crit. Rev. Clin. Lab. Sci. 1988; 26: 97-152Crossref Scopus (54) Google Scholar, 6Knight W.A.I., II Livingston R.B. Gregory E.J. McGuire W.L. Cancer Res. 1977; 37: 4669-4671PubMed Google Scholar, 7Sigurdsson H. Baldetorp B. Borg A. Dalberg M. Ferno M. Killander D. Olsson H. N. Engl. J. Med. 1990; 322: 1045-1053Crossref PubMed Scopus (313) Google Scholar). Studies of breast cancer cell lines (8Weigel R.J. deConinck E.C. Cancer Res. 1993; 53: 3472-3474PubMed Google Scholar) and primary tumors (9Barrett-Lee P.J. Travers M.T. McClelland R.A. Luqmani Y. Coombes R.C. Cancer Res. 1987; 47: 6653-6659PubMed Google Scholar, 10Carmeci C. deConinck E.C. Lawton T. Bloch D.A. Weigel R.J. Am. J. Pathol. 1997; 150: 1563-1570PubMed Google Scholar) have indicated that transcription of the ERα gene plays an important role in regulating the expression of ERα. Thus, understanding transcriptional regulation of the ERα gene likely critical the of hormone-responsive breast cancers. of the ERα gene and involves activity of several promoters M. J. M.T. R.C. J. PubMed Scopus Google Scholar, R. R. J. 1993; PubMed Scopus Google Scholar, 1996; PubMed Scopus Google Scholar, D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). promoter have that ERα expression in breast cancer cell lines and likely to that have a specific cell E.C. Weigel R.J. PubMed Scopus Google Scholar, M. 1997; PubMed Scopus Google Scholar, H. T. S. Res. PubMed Scopus Google Scholar, R.J. deConinck E.C. Google Scholar, M. J. A. PubMed Google Scholar). There to a of that with the ERα promoter with E.C. Weigel R.J. PubMed Scopus Google Scholar, M. 1997; PubMed Scopus Google Scholar, H. T. S. Res. PubMed Scopus Google Scholar) R. PubMed Scopus Google Scholar) There evidence that ERα transcription S. R. J. 1997; PubMed Scopus Google N. M. A. 1997; PubMed Scopus Google Scholar). that the of ERα expression in ERα-negative breast cancer cell lines and tumors by of in the 5′ of the ERα gene Y. J. H. S. N. Cancer Res. Google H. S. S. J. N. Clin. Cancer Res. 1996; Google Scholar). The ERα transcription at a cap at the of exon 1 (1Green S. Walter P. Kumar V. Krust A. Bornert J.M. Argos P. Chambon P. Nature. 1986; 320: 134-139Crossref PubMed Scopus (1938) Google Scholar). 1 a region the that of the ERα Studies in ERα-positive breast cancer cell lines have that transcription at exon 1 for of all ERα R.J. deConinck E.C. Google Scholar, C. M. V. PubMed Google Scholar). A of the ERα promoter a that to sites in the untranslated region of exon 1 and the ERα promoter E.C. Weigel R.J. PubMed Scopus Google Scholar, Weigel R.J. Res. PubMed Scopus Google Scholar). was to a of the AP2 of transcription and been AP2γ Weigel R.J. Sci. S. A. 1997; PubMed Scopus Google Scholar). ERα transcripts at cap sites of exon 1 and a at in exon 1 D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). of exons have evidence that are and that all alternate 5′ exons are been reported to have two cap sites rise to alternate 5′ exons of R. R. J. 1993; PubMed Scopus Google Scholar). The and of exon the at to cap of We two alternate ERα transcripts E and H D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). the E and H transcripts are in ERα-positive breast cancer cell primary breast ERα-positive cell and The of the E and H transcripts of ERα were by and exons were reported to in a of C. M. V. PubMed Google Scholar). The of exon E was to at The H was to two and by an of D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). The genomic of the H exons was not was to at least 5′ to exon 1 D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). exon been 1996; PubMed Scopus Google Scholar). was reported to to an exon with exon and was that exon 5′ exon D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). to the of the ERα promoters in breast a of the genomic structure of the 5′ of the ERα gene the alternate ERα transcripts E and H was have been that generated a contig map that includes all known ERα exons. The exon was to of exon and exon was 5′ to exon with the known exons of the ERα gene that a region of the ERα was to a genomic region of By using S1 nuclease and the cap sites for exons E and H have been of the alternate exons was to associated with DNase I-hypersensitive sites specific to cells ERα. The DNase I-hypersensitive site, HS1, was to the binding sites for AP2γ in the untranslated of exon 1 and was invariably in the chromatin structure of ERα-positive cells. human mammary epithelial cells AP2γ expression induced the HS1-hypersensitive and the ERα was dependent upon the region of the promoter containing the HS1 site. These evidence for a critical role for AP2γ in the oncogenesis of hormone-responsive breast cell lines were from were in minimal essential media with fetal and were from and were a from J. were in media V. D. V. R. Sci. S. A. 1990; PubMed Scopus Google Scholar). cells were at in containing genomic from the 5′ region of the human ERα gene were by of with to the human ERα exons and with from a human were from from of ERα exons and were for and were from genomic using and and The an of for by of for for and for and with a of for for were and by with to specific were in and at for 1 of were the of was to and each was to and for at the were in at and in at were by to of the in the were from A of was from each using the for by from were with and D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar) for the of ERα exon and with and for the of ERα exon from containing of the ERα region was from using a from by the of was in with the and to in at with from 1 to were by and were from from were to using by the The were with to the locations of the ERα exons to the sites in each were the ERα exon and to ERα exon 1996; PubMed Scopus Google Scholar) and to the ends of the genomic were The of the ends of the were by of S1 nuclease were R.J. deConinck E.C. Google Scholar) with of the for was from cells using a to the The for of the ERα transcripts at the exon promoter was by from a that exon of The was from genomic using the the and the 5′ were that the was a to the was using in the of the was a to The for of the ERα transcripts from the promoter associated with exon E was by using The was and was to the E.C. Weigel R.J. PubMed Scopus Google Scholar) a The of the was by with and the was from the by a The was from the using a DA the E was to of at S1 was and the were at for 1 The were and the were with a were by from cells was by using the from by the transcription was with in exon 1 at The for the of was to in exon 1 of A of amplification was using the and for exons E and were using a The of the 5′ of each was by DNase was in a of ERα-positive and ERα-negative cell were and with phosphate-buffered saline The cells were with A 1 and in of A with The cells were in a using of a was by were and in of A of of DNase were and to and the were for The were by of to of to and to 1 the were at protein was by each with and the were in and the at was of each were with the at of sites exon the were using and to for The were with the exon of sites exons were to was and with the exon to the for the of an was generated by a of AP2γ in with to a A to was generated by and in in the The of the was by the from The was cells and the of a protein of the was by of the protein was induced with of the cells in the of were with with and the protein with the of The protein was and were generated by of a was by a to to the of the and a with of the were using were E.C. Weigel R.J. PubMed Scopus Google Scholar). of was The to was from to AP2γ and the AP2γ and were a By using a AP2γ from a expression Weigel R.J. Sci. S. A. 1997; PubMed Scopus Google Scholar) AP2γ cDNA was from the at to the at using a 5′ containing a and a containing an site. cDNA was from the to the using an cDNA Weigel R.J. Res. PubMed Scopus Google Scholar) was using a 5′ containing a and a containing an site. The AP2γ and cDNA were the of The DA J. B. Sci. S. A. PubMed Scopus Google Scholar) with to and the protein that by and 1 of was at two with and with and by of and of of DA J. B. Sci. S. A. PubMed Scopus Google Scholar) cells was in at and using a were for and was by with were and was using the to the and were DA J. B. Sci. S. A. PubMed Scopus Google Scholar) with several cells were in in with that cells by the of each of and were was with of in of and at for to the the cells were with of the were to with and the cells. at for the was with of and to the were by for expression at of the cells were fluorescent and from the were in of and to of and were by cells in with of of from to in a at cells were with of in and to the were for and expression at were of and to of was to cells in a and the cells were at the cells were at least was by and more of infection were at an of to A of infection was at an of using cells in were at and of in of the was by using a of in a at was in with an and 1 of serum and at for were by expression in cells, and in of in cells and in to the of and was from the using the to the for was to amplification using of for AP2γ and and for for were of from the and from AP2γ pair pair of two from the pair pair 1 was of and and pair was of and pair the for was using pair are and The a of cells for each was in The media were from the and the cells were with of were at an of for at were for DNase The ERα promoter have been E.C. Weigel R.J. PubMed Scopus Google Scholar). The and were and However, that the 5′ of the are at to the cap site. in were in using and expression was using expression Weigel R.J. Res. PubMed Scopus Google Scholar). We alternate 5′ exons of the human ERα gene that were in breast cancer cell lines and primary breast tumors D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). However, genomic with genomic to a contig the to the was exon and the in exon The of the exon 1996; PubMed Scopus Google Scholar) not been to the 5′ exons and a was using exons and the in the from exon and exon and was likely to the two exons. to a specific for exon were that from exons and not exon to a for the exon C. was to a to the of the ERα and to the in the two in results using genomic that exon was at least of exon D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). The results from and that exon was more of exon and that the the cap for exon and the cap for exon 1 was that the exon was a and of exon The of the alternate 5′ exons of the human ERα gene that are ERα promoters that promoter have been for promoters transcription at exons 1 E.C. Weigel R.J. PubMed Scopus Google Scholar) and H. T. S. Res. PubMed Scopus Google have been promoters that in expression of exons E to further promoters expression of two alternate to the cap sites of the E and H transcripts were using S1 nuclease and The results of are in the S1 was to a several of the of the cDNA for ERα transcripts with exon D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). The of with 5′ ends and of the 5′ of the cDNA for that the cap sites of been by S1 nuclease was A was the of using a in exon not with were to the and the results were with the S1 nuclease data The the of the the locations of from to the S1 a in with the ends by S1 of were that and of the from cDNA to of the S1 and to the S1 These results demonstrate that exon a ERα cap with sites E was an 5′ exon from a cDNA and was localized exon and exon 1 D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google Scholar). The of exon E was of the transcriptional for the ERα to that ERα transcripts have a cap associated with transcription at exon a to that for exon was A from the of exon E to several was to S1 nuclease of the several was for exon A was that to an of the from the cDNA for exon E were the of was from the cDNA 5′ The to The of from cells using exon two of and not of the were and the base with the S1 data several the of S1 and the an with to by S1 A of 5′ ends an to the to S1 B. the S1 nuclease are from the in the S1 nuclease results and results are in The of DNase I-hypersensitive sites been to to the of binding by transcription in transcriptional regulation of a gene C. Nature. PubMed Scopus Google Scholar). DNase I-hypersensitive sites important the of the transcriptional data A. S. J. 1993; PubMed Scopus (54) Google Scholar) DNase I-hypersensitive sites exon 1 that were specific to ERα-positive cells, HS1 the cap for exon at and at to the cap for exon A of results and localized the sites with more The was the region of exon 1 at A was at and a was at with each of sites was specific to ERα-positive cells, and have the The of HS1 with binding sites for were in a promoter of the ERα promoter E.C. Weigel R.J. PubMed Scopus Google Scholar). to associated with exon and to the promoter known the H. T. S. Res. PubMed Scopus Google Scholar) for exon a exon of at a at R. R. J. 1993; PubMed Scopus Google Scholar) that two alternate transcriptional sites. the exon of the of exon to exon E and to the promoter transcription at cap site. DNase I-hypersensitive was using an exon of from and cells to in transcription of the H of a in and with the of the from the at was in with DNase a that specific to ERα-positive cells to a of exon of a at in cell A of was in with DNase not in to the in were in of and and not specific to ERα-positive cells. These sites to the locations indicated the the to a of exon and to a exon The of the HS1-hypersensitive that of chromatin structure for transcription from the ERα promoter. were the HS1 invariably in cells that express ERα. The chromatin structure of a of ERα-positive and ERα-negative cell lines was for the of the HS1 A. S. J. 1993; PubMed Scopus (54) Google Scholar). the results of an of the HS1 in an of cell The ERα-positive breast cell lines and all the HS1 site. The ERα-positive cancer cell the HS1-hypersensitive site. the HS1 was not to present in an of the chromatin structure of the ERα-negative cell lines with the results in of the HS1 in cell lines a the expression of ERα and the of the HS1 site. in cell lines have that each of the cell lines that demonstrate the HS1 and been to overexpress cell lines that the HS1 and express of the AP2 E.C. Weigel R.J. PubMed Scopus Google Scholar, D.A. Weigel R.J. Res. 26: PubMed Scopus Google Scholar). that the HS1 generated by AP2 binding to chromatin in the ERα promoter. The of HS1 to the untranslated region of exon 1 and with the of binding sites for the AP2 transcription E.C. Weigel R.J. PubMed Scopus Google Scholar). of the ERα promoter indicated that AP2γ are to transcription from the ERα promoter by binding to the AP2 sites in the untranslated of exon 1 E.C. Weigel R.J. PubMed Scopus Google Scholar, Weigel R.J. Res. PubMed Scopus Google Scholar). AP2 in regulation of the ERα gene in cells, an was in the to and The specific for AP2γ and not of nuclear that the of AP2 activity in with the indicated that of the AP2 activity in nuclear by the that and of AP2γ that of the AP2 activity in cells promoter an important role for AP2γ in regulating the expression of the ERα promoter in ERα-positive cells E.C. Weigel R.J. PubMed Scopus Google Scholar). HS1 was specific to the chromatin of ERα-positive cells, and the of HS1 with the of the sites. These two to that binding of AP2γ to sites in the ERα promoter the HS1 site. express minimal of ERα protein and are to was that AP2γ and was to of AP2γ in of with induced of AP2 was with AP2 However, AP2 activity was in with AP2γ expression was to the HS1-hypersensitive in ERα exon 1 However, and were not induced by AP2γ of with not of sites in the ERα exon 1 region These were using an that the results were not that binding of AP2γ of the chromatin structure of the ERα promoter and inducing the HS1 a of the chromatin in ERα-positive cells. Expression of the ERα gene was in in AP2 expression was induced by infection with changes in the of ERα expression were in not that changes in chromatin structure are to ERα expression in mammary epithelial cells. were with a in the ERα promoter was of the results of in an AP2 expression was with ERα promoter in the activity in The activity of was not by of an AP2γ expression ERα promoter containing the untranslated to of expression in that was to the However, AP2γ was to the ERα promoter in and induced expression from the promoter by ERα promoter that the untranslated the region of the promoter containing the HS1-hypersensitive site. expression in the containing the untranslated However, in to by These results demonstrate that AP2γ the ERα promoter in by with the region of the promoter the HS1-hypersensitive site. cancers that express ERα are more likely to occur in women (4Jordan V.C. Wolf M.F. Mirecki D.M. Whitford DA Weshons W.V. CRC Crit. Rev. Clin. Lab. Sci. 1988; 26: 97-152Crossref Scopus (54) Google are associated with a prognosis W.A.I., II Livingston R.B. Gregory E.J. McGuire W.L. Cancer Res. 1977; 37: 4669-4671PubMed Google H. Baldetorp B. Borg A. Dalberg M. Ferno M. Killander D. Olsson H. N. Engl. J. Med. 1990; 322: 1045-1053Crossref PubMed Scopus (313) Google and are more likely to respond to hormonal therapy (4Jordan V.C. Wolf M.F. Mirecki D.M. Whitford DA Weshons W.V. CRC Crit. Rev. Clin. Lab. Sci. 1988; 26: 97-152Crossref Scopus (54) Google Scholar, 5Bradbeer J.W. Kyngdon J. Clin. Oncol. 1983; 9: 31-34PubMed Google Scholar) tumors that not express the ERα-positive breast cancers overexpress ERα protein and have more ERα mammary epithelial cells D. R. C. Coombes R.C. Cancer Res. Google Scholar). Studies of breast cancer cell lines (8Weigel R.J. deConinck E.C. Cancer Res. 1993; 53: 3472-3474PubMed Google Scholar) and primary (9Barrett-Lee P.J. Travers M.T. McClelland R.A. Luqmani Y. Coombes R.C. Cancer Res. 1987; 47: 6653-6659PubMed Google Scholar, 10Carmeci C. deConinck E.C. Lawton T. Bloch D.A. Weigel R.J. Am. J. Pathol. 1997; 150: 1563-1570PubMed Google Scholar) that transcriptional regulation a critical of of ERα The genomic map of the 5′ region of the ERα in a map of the ERα cap sites and the of in transcriptional Thus, data the for a of the alternate ERα promoters in breast The site, HS1, invariably to a of chromatin in cell lines that express ERα. The of the HS1 to binding sites for the AP2 transcription in the ERα and the HS1 generated in by expression of the AP2γ transcription We have further that AP2γ the ERα promoter in by with the region of the promoter the HS1 site. ERα expression for results further evidence that of AP2γ a critical in the oncogenesis of hormone-responsive breast The exons of the ERα gene the ERα protein and a region of of genomic S. Chambon P. J. 1988; PubMed Scopus Google Scholar). We have developed a contig map that includes all of the known 5′ exons of the ERα gene that an to the ERα gene the of the ERα to We were to that exon of the region of the ERα gene and that the exon and the in exon 1 been a ERα exon 1996; PubMed Scopus Google Scholar). been reported to to exon D.A. C. deConinck E.C. Weigel R.J. J. 1997; PubMed Scopus Google and was that exon was in the of exon to the genomic for exon in a C. M. V. PubMed Google Scholar). The two alternate ERα E and are with cap sites that are ERα promoters expression of the ERα are cap sites for exons and exon by the S1 nuclease and results the of exon cap sites are for exon to two of cap sites by cap sites are a of with the of associated with the exon E that the ERα gene by several The for a gene promoters that the protein not A H. S. R. M. V. J. PubMed Google Scholar) the expression of an of ERα that the of the The ERα trans-activation of the ERα was by an that exon 1 and to exon likely that of alternate cap sites to expression of ERα with alternate There expression that the of alternate cap sites. the genomic cap and sites associated with exons an important the regulation of alternate ERα DNase I-hypersensitive sites are of chromatin that are and to DNase C. Nature. PubMed Scopus Google Scholar). These sites to the of important of gene sites specific to transcription of ERα are each of the ERα cap sites. However, from a cap site, and a the of a to regulation of more results are in with that have sites of the ERα gene exon 1 A. S. J. 1993; PubMed Scopus (54) Google Scholar). a site, been that specific to ERα-positive cells. The of exon and a expression of ERα transcription at exon The HS1 been localized to the untranslated of the ERα promoter in exon 1 and in all ERα-positive breast and cell lines and not a of the chromatin structure of ERα-negative cell lines and The of the HS1 to the region of the ERα promoter that was in a to for transcription E.C. Weigel R.J. PubMed Scopus Google Scholar, Weigel R.J. Res. PubMed Scopus Google Scholar). region of a E.C. Weigel R.J. PubMed Scopus Google that was to in ERα-positive breast and ERα-positive cancer cell The was and to to AP2γ Weigel R.J. Sci. S. A. 1997; PubMed Scopus Google Scholar). in nuclear of AP2γ AP2 These two AP2 have binding and are to expression from the ERα promoter Weigel R.J. Res. PubMed Scopus Google Scholar). The data that and AP2γ are to the HS1-hypersensitive in that are to changes in the chromatin structure that known to associated with transcription of the ERα We have further that AP2γ the ERα promoter in and that trans-activation the region of the promoter that the HS1 site. These results evidence that AP2γ an important role in regulating transcription of the ERα gene by chromatin structure of the promoter. the genomic structure and expression of the ERα gene in to hormone-responsive breast cancer a cell to the that to a hormone-responsive Overexpression of AP2 to important by data that of AP2γ in breast cancer compared with mammary epithelial cells B. J. A. M. D. P. H. B. T. Cancer Res. Google Scholar). a expression and the ERα-positive breast cancer B. J. A. M. D. P. H. B. T. Cancer Res. Google Scholar). However, were not to an in ERα in with the not not R. PubMed Scopus Google Scholar) have reported the of in ERα-negative cells that expression of ERα. HS1 sites are present the promoter region of the ERα gene that were not generated by expression of AP2 that to of the ERα gene in in the regulation of ERα gene transcription an for further changes of chromatin structure that are to of ERα. in to are to of ERα to the of oncogenesis of hormone-responsive breast