Estrogen signaling: ERBB2 hangs in the balance
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Exclusive to Signaling Gateway
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The sensitivity of breast cancer tumors to tamoxifen depends upon the inhibition and activation of ERBB2 gene expression, which is controlled by the competitive binding of PAX2 and AIB-1 to a cis-regulatory element.
Tamoxifen is an analogue of the hormone estrogen and is widely used in the treatment of estrogen receptor-positive breast cancer. Tamoxifen and estrogen both bind to estrogen receptor to repress the transcription of ERBB2 (epidermal growth factor (EGF)-receptor-related protein tyrosine kinase B2). Tamoxifen resistance is characterized by elevated levels of ERBB2 and is relatively common in some breast cancer tumors. However, a molecular mechanism linking estrogen receptor signaling, ERBB2 expression and tamoxifen resistance has remained elusive. Carroll and colleagues now report in Nature that ERBB2 expression is controlled by the balance between the estrogen receptor co-activator AIB-1 (amplified in breast cancer-1) and the transcription factor PAX2 (paired box 2 gene product), which both competitively bind to the same ERBB2 regulatory element.
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A novel estrogen receptor-α binding site was identified in intron 4 of the longer ERBB2 isoform. PAX2 is known to be expressed in certain breast cancers and was shown to interact with estrogen receptor. The authors found that PAX2 and estrogen receptor both bound to the same site on ERBB2 following tamoxifen or estrogen treatment, and observed a reduction in ERBB2 mRNA levels upon PAX2 binding. Conversely, small interfering RNA (siRNA)-mediated knockdown of PAX2 derepressed tamoxifen- and estrogen-mediated inhibition of ERBB2 expression and allowed the proliferation of estrogen receptor-positive breast cancer cell lines. Thus, PAX2 appears to act as an ERBB2 transcriptional repressor.
The authors found that the response of breast cancer cells to tamoxifen is regulated by competition between AIB-1 and PAX2 binding to cis-regulatory elements in ERBB2. Indeed, a decrease in PAX2 expression in tamoxifen-resistant (Tam-R) cells correlated with an increase in ERBB2 expression. Estrogen receptor was recruited to ERBB2, whereas PAX2 binding decreased, in response to tamoxifen with a similar efficiency in Tam-R and tamoxifen-responsive cells. Conversely, AIB-1 binding increased in Tam-R cells in response to tamoxifen treatment. Overexpression of PAX2 reduced AIB-1 binding to ERBB2, restored tamoxifen-mediated repression of ERBB2 and inhibited cellular proliferation. These findings suggest that AIB-1-mediated ERBB2 expression is antagonized by competitive PAX2 binding.
Immunohistochemical staining of tamoxifen-treated estrogen receptor-positive breast cancer tumors demonstrated that PAX2 expression in the absence of AIB-1 correlated with cancer recurrence-free patient survival and a low rate of ERBB2 expression. Patients with PAX2/AIB-1-positive tumors had a higher rate of cancer recurrence. Thus, levels of PAX2 and AIB-1 expression can serve as prognostic indicators of patients' response to tamoxifen treatment. Further study is required in order to define the mechanism of PAX2 regulation in response to estrogen and tamoxifen.
Anna S. Kushnir
Nature Publishing Group
Reference
- Hurtado, A. et al. Regulation of ERBB2 by oestrogen receptor–PAX2 determines response to tamoxifen. Nature 456, 663-666 (2008) | Article | PubMed |
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