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Transcriptional activation of breast cancer-associated gene 2 by estrogen receptor

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Abstract

RNF115, or Breast Cancer-Associated Gene 2 (BCA2), encodes a RING-finger ubiquitin E3 ligase, expression of which was associated with estrogen receptor (ER)-positive status in human breast tumors. Although the BCA2 promoter contains several estrogen response element (ERE) half-sites, the role of ER in the regulation of BCA2 transcription has not been reported. The aim of this study is to investigate the molecular mechanism by which estrogen regulates BCA2 transcription. BCA2 mRNA and protein levels were examined by RT-PCR and Western blot analysis, respectively, and localization was assessed by immunofluorescence. BCA2 promoter activity in response to E2 was tested by a dual luciferase reporter assay and ER binding to the BCA2 promoter was examined by chromatin immunoprecipitation assay. We found that BCA2 mRNA and protein levels are regulated by estrogen in ER-positive MCF7 breast cancer cells and MDA MB 231 cells stably transfected with ER. Estrogen treatment in hormonal depleted MCF7 and MDA MB 231/ER stably transfected cells resulted in increased nuclear ER and cytoplasmic and nuclear BCA2 staining. Cycloheximide is not able to inhibit BCA2 mRNA levels, suggesting potential BCA2 regulation at the transcriptional level. Anti-estrogens like tamoxifen and ICI 182 178 counteracted E2-induced BCA2 protein and knockdown of ER by ER siRNA resulted in a significant decrease in BCA2 protein and a lower nuclear expression pattern. Estrogen treatment lead to a significant increase in BCA2 promoter response, associated with increased binding of ER to the ERE region of the BCA2 promoter. BCA2 is therefore a newly identified transcriptional target of estrogen receptor.

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Acknowledgments

This study was partially supported by the National Cancer Institute at the National Institutes of Health (5R01CA127258-05, 1R01CA120009, and 3R01CA120009-04S1) to QPD and Postdoctoral Training Grant by Susan Komen Foundation (KG101529) to FRK; the Wayne State University; Karmanos Cancer Center, Detroit, MI.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Barbara Ann Karmanos Cancer Institute and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, 540.1 Hudson Webber Cancer Research Building, Mail Code HW05AO, 4100 John R Road, Detroit, MI, 48201-2013, USA

    Fathima R. Kona, Karri Stark, Luke Bisoski, Daniela Buac, Qiuzhi Cui & Q. Ping Dou

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  1. Fathima R. Kona
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  2. Karri Stark
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  3. Luke Bisoski
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  4. Daniela Buac
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  5. Qiuzhi Cui
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  6. Q. Ping Dou
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Corresponding author

Correspondence to Q. Ping Dou.

Additional information

In memory of Professor Angelika Burger who initiated this project. Professor Burger’s research focused on the identification and validation of new molecular targets for the treatment of breast cancer. Dr. Burger’s particular interest was in the investigation of the role of the ubiquitin E3 ligase, BCA2, in breast cancer development and to further design and develop small molecular inhibitors targeting BCA2. Dr. Burger was a very gifted researcher, who lost her personal battle with cancer in May, 2011. This article is dedicated to her as a token of our appreciation of a truly outstanding researcher.

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Kona, F.R., Stark, K., Bisoski, L. et al. Transcriptional activation of breast cancer-associated gene 2 by estrogen receptor. Breast Cancer Res Treat 135, 495–503 (2012). https://doi.org/10.1007/s10549-012-2107-4

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  • DOI: https://doi.org/10.1007/s10549-012-2107-4

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