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HEXIM1 is a critical determinant of the response to tamoxifen

Oncogene volume 30, pages 3563–3569 (2011)Cite this article

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Abstract

Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER)-positive patients. We have previously reported that hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) inhibits ERα activity by competing with ERα for binding to cyclin T1, a subunit of positive transcription elongation b (P-TEFb). This results in the inhibition of the phosphorylation of RNA polymerase II (RNAPII) at serine 2 and the inhibition of transcription elongation of ERα target genes. As HEXIM1 can inhibit ER activity, we examined whether it has a critical role in the inhibitory effects of tamoxifen on ER. We observed that tamoxifen-induced HEXIM1 recruitment to the promoter region of ER target genes and decreased the recruitment of cyclin T1 and serine 2 phosphorylated RNAPII to the coding regions of these genes. Conversely, in cells wherein HEXIM1 expression has been downregulated we observed attenuation of the inhibitory effects of tamoxifen on estrogen-induced cyclin T1 recruitment to coding regions of ER target genes. As a consequence, downregulation of HEXIM1 resulted in the attenuation of the repressive effects of tamoxifen on estrogen-induced gene expression and proliferation. Conferring clinical relevance to our studies is our analysis of human breast cancer tissue samples that indicated association of lower expression of HEXIM1 with tumor recurrence in patients who received tamoxifen. Our studies provide a better understanding of the mechanistic basis for the inhibitory effect of tamoxifen on ER activity and may suggest new therapeutic targets for the treatment of tamoxifen-resistant breast cancer.

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Abbreviations

CCND1:

cyclin D1

ERα:

estrogen receptor alpha

E2:

17-beta estradiol

HEXIM1:

hexamethylene-inducible gene-1

P-TEFb:

positive transcription elongation factor b

RNAP II:

RNA polymerase II

TOT:

trans-hydroxy-tamoxifen

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Acknowledgements

We thank Wei Wang (CWRU Department of Epidemiology and Biostatistics) for help with construction of graphs representing the relationship between disease recurrence and expressions levels of HEXIM1 in breast tissue. This work was supported by National Institute of Health grant CA92440 to MMM and American Cancer Society grant RSG CCE-110689 to J.J.P.

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Authors and Affiliations

  1. Department of Pharmacology, Case Western Reserve University Cleveland, Cleveland, OH, USA

    W Ketchart, N Ogba & M M Montano

  2. Department of Pathology, Case Western Reserve University Cleveland, Cleveland, OH, USA

    A Kresak

  3. Department of Epidemiology and Biostatistics, Case Western Reserve University Cleveland, Cleveland, OH, USA

    J M Albert

  4. Division of General Medical Science- Oncology Case Comprehensive Cancer Center, Case Western Reserve University Cleveland, Cleveland, OH, USA

    J J Pink

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  1. W Ketchart
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  2. N Ogba
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  3. A Kresak
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  6. M M Montano
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Correspondence to M M Montano.

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Ketchart, W., Ogba, N., Kresak, A. et al. HEXIM1 is a critical determinant of the response to tamoxifen. Oncogene 30, 3563–3569 (2011). https://doi.org/10.1038/onc.2011.76

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