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Modulation of Aromatase Expression in the Breast Tissue by ERR-1 Orphan Receptor¹

Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010

We have previously identified a silencer element (S1) that is situated between promoters I.3 and II of the human aromatase gene and that down-regulates the action of these promoters. We recently applied the yeast one-hybrid approach to screen a human breast tissue hybrid cDNA expression library for genes encoding the proteins binding to the silencer region. Most proteins identified from this approach belong to the nuclear receptor superfamily. Fifty % of the positive clones encode for ERR-1, and other positive clones include EAR-2, EAR-3 (COUP-TF1), RAR, and p120E4F. Because ERR-1 was found to be the major protein interacting with S1, we decided to examine the regulatory action of ERR-1 on promoter I.3 of the human aromatase gene. Using a reporter plasmid that includes the aromatase genomic fragment containing promoter I.3 and S1, ERR-1 was found to have a positive regulatory function in breast cancer SK-BR-3 cells. Gel mobility shift assays have confirmed that ERR-1 binds to S1 in a dose-dependent manner, and DNase I footprinting analysis has revealed that ERR-1 binds to a region, 5'-AAGGTCAGAAAT-3', which is within S1 and between 96 and 107 bp relative to the transcriptional start site of promoter I.3. In addition, despite the fact that the nuclear receptor SF1 was shown previously to bind to the same site and to mediate a cAMP response in ovary, our yeast one-hybrid screening did not find any SF-1 clones. Gel mobility shift assays further revealed that SF-1 can bind to the silencer element with an affinity copmarable with ERR-1. Because our reverse transcription-PCR analysis was not able to detect SF1 mRNA in breast cancer tissue or in SK-BR-3 cells, it is thought that SF1 protein is not expressed in breast cancer tissue. Two ERR-1 RNA variants with differences at the 5'-end have been reported. Our reverse transcription-PCR analysis identified the shorter variant in 28 of 32 breast tumor specimens and the longer variant in only 1 specimen. In addition, the shorter variant was detected in breast cancer SK-BR-3 cells as well as in a breast tumor fibroblast line WS3TF. The results suggest that ERR-1 is one of the nuclear proteins interacting with S1 in breast cancer tissue. It is thought that the silencer element in the human aromatase gene may function differently in different tissues because of distinct expression patterns of transcription factors.

¹ This research was supported by NIH Grant CA44735 and University of California BCRP Grant 1RB0118. S. C. and D. Z. are members of the City of Hope Breast Cancer Program (Grant CA 65767). C. Y. is a predoctoral student of the Third Military Medical University, Chongquing, China.

² These authors contributed equally to this study.

³ To whom requests for reprints should be addressed, at City of Hope Beckman Research Institute, 1450 East Duarte Road, Duarte, CA 91010-0269. Phone: (626) 359-8111, extension 2601; Fax: (626) 301-8186; E-mail: schen@smtplink.coh.org.

Received 9/23/98. Accepted 10/29/98.

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