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Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers

Oncogene volume 30, pages 4327–4338 (2011)Cite this article

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Abstract

Prostate cancer and breast cancer are the most common malignancies in the western world. Androgen receptor (AR) and PTEN both have been well documented to have important roles in prostate carcinogenesis. In contrast, AR and PTEN in breast carcinogenesis have not been well studied. Furthermore, the crosstalk and connection between those two pathways remain unclear. Increased AR expression in prostate cancers, combined with decreased PTEN expression, portends a poor clinical outcome. Paradoxically, both high AR and high PTEN levels, detected by immunohistochemistry, in primary breast carcinomas have been associated with better disease-free survival. Here, we performed in silico analysis of publicly available microarray data sets from prostate or breast carcinomas. We found an inverse correlation between AR and PTEN transcript expression in prostate cancer tissues in contrast to the positive correlation in breast cancer. These data led us to hypothesize that AR may directly affect PTEN transcriptional regulation in prostate and breast cancer cells. Here, we show for the first time that AR inhibits PTEN transcription in prostate cancer cells, whereas AR upregulates PTEN transcription in breast cancer cells, which mechanistically explains both the immunohistochemical PTEN–AR expressional data noted in clinical trials and in our in silico analysis of the transcriptomes of breast and prostate cancers. In addition, we have fine-mapped the AR-binding motif within the PTEN promoter. Here we show that, in patients with Cowden syndrome, an inherited cancer syndrome caused by germline mutations scattered throughout PTEN, point variants affecting the 3′ end of the AR-binding motif result in abrogation of androgen-mediated transcriptional regulation of PTEN expression. We may speculate that the differential AR effect on PTEN may begin to explain organ-specific and perhaps sex-specific neoplasia predisposition in Cowden syndrome, as well as why only a fraction of women with germline PTEN mutations develop breast cancer, depending on the androgen steroid milieu and levels.

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Acknowledgements

We are grateful to Dr George Stark for critical review of manuscript drafts and for helpful discussions. This work was supported, in part, by the William Randolph Hearst Foundations and Susan G Komen for the Cure Breast Cancer Research Foundation. CE is the Sondra J and Stephen R Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic, was a Doris Duke Distinguished Clinical Scientist and is an American Cancer Society Clinical Research Professor, generously funded, in part, by the FM Kirby Foundation.

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Authors and Affiliations

  1. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Y Wang, T Romigh, X He, M-H Tan, M S Orloff & C Eng

  2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    M S Orloff, R H Silverman, W D Heston & C Eng

  3. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    R H Silverman & W D Heston

  4. CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    R H Silverman, W D Heston & C Eng

  5. Stanley Shalom Zielony Institute for Nursing Excellence, Cleveland Clinic, Cleveland, OH, USA

    C Eng

  6. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    C Eng

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  1. Y Wang
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Correspondence to C Eng.

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Wang, Y., Romigh, T., He, X. et al. Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. Oncogene 30, 4327–4338 (2011). https://doi.org/10.1038/onc.2011.144

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