Research highlights
Signalling: ERBB2 hangs in the balance
Nature Reviews Cancer 9, 1 (01 January 2009) | doi:10.1038/nrc2570
Standfirst
The resistance of oestrogen receptor (ER)-positive breast cancers to tamoxifen is associated with increased expression levels of the oncogene ERBB2. The molecular mechanism that links ER signalling, ERBB2 expression and tamoxifen resistance has remained elusive. However, Jason Carroll and colleagues report in Nature that ERBB2 expression can be controlled by the ER co-activator AIB1 (amplified in breast cancer 1) and the transcription factor PAX2 (paired box 2 protein), and the differential expression of these two proteins determines the response to tamoxifen.
MACMILLAN\Paul BricknellA 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.
Are these findings relevant to breast cancer treatment? Immunohistochemical staining of tamoxifen-treated ER-positive breast cancers demonstrated that expression of PAX2 correlated with improved recurrence-free survival compared with PAX2-negative cancers. In addition, cancers that expressed both PAX2 and AIB1 were associated with a poorer prognosis than those that were AIB1 negative.
The authors propose that expression levels of PAX2 might also be used as a prognostic indicator of response to tamoxifen, similar to the combined expression of ERBB2 and AIB1, which is known to predict resistance.
ORIGINAL RESEARCH PAPER
- Hurtado, A. et al. Regulation of ERBB2 by oestrogen receptor–PAX2 determines response to tamoxifen. Nature 12 Nov 2008 (doi:10.1038/nature07483) | Article |
FURTHER READING
- 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) | Article |
