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ERBB2 hangs in the balance

Nature Reviews Cancer volume 9, pages 12–13 (2009)Cite this article

A novel ER binding site has recently been identified in an intron of ERBB2. The authors found that this site and several other ER binding sites also contained a PAX2 binding site. Further investigations showed that PAX2 could interact with ER and that both PAX2 and ER bound to this intronic site in ERBB2 following treatment with either tamoxifen or oestrogen. The authors confirmed this ER binding site as the cis-regulatory element for ERBB2. Binding of PAX2 resulted in reduced levels of ERBB2 mRNA and, conversely, small interfering RNA-mediated knockdown of PAX2 prevented tamoxifen- or oestrogen-mediated inhibition of ERBB2. Thus, PAX2 seems to act as an ERBB2 transcriptional repressor.

Tamoxifen-resistant ER-positive breast cancers are also known to overexpress AIB1, so Carroll and colleagues investigated whether competition between AIB1 and PAX2 might be involved in the regulation of ERBB2 expression. A decrease in PAX2 expression in tamoxifen-resistant cells correlated with an increase in ERBB2 expression, and AIB1 binding increased in tamoxifen-resistant cells in response to tamoxifen treatment. Moreover, the overexpression of PAX2 reduced AIB1 binding to ERBB2, restored tamoxifen-mediated repression of ERBB2 and inhibited cellular proliferation. These findings suggest that AIB1-mediated ERBB2 expression is antagonized by competitive PAX2 binding to this cis-regulatory element.

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References

ORIGINAL RESEARCH PAPER

  1. Hurtado, A. et al. Regulation of ERBB2 by oestrogen receptor–PAX2 determines response to tamoxifen. Nature 12 Nov 2008 (doi:10.1038/nature07483)

FURTHER READING

  1. Green, K. A, and Carroll, J. S. Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state. Nature Rev. Cancer 7, 713–722 (2007)

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    Anna S. Kushnir

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  1. Anna S. Kushnir
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Kushnir, A. ERBB2 hangs in the balance. Nat Rev Cancer 9, 12–13 (2009). https://doi.org/10.1038/nrc2570

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