Most cases of breast cancer are dependent on oestrogen for tumour progression, and treatment with tamoxifen, which modulates the oestrogen receptor (ER), has been successful in considerably reducing deaths from breast cancer. However, many patients become resistant to tamoxifen and C. Kent Osborne and colleagues now show that overexpression of an oestrogen receptor co-activator, AIB1, together with high expression of a member of the epidermal growth-factor-receptor family, ERBB2 (also known as HER2/neu), in ER-positive breast cancer patients is associated with resistance to tamoxifen.

Osborne et al. examined tumour samples from 316 breast cancer patients with long-term follow-up. In the 187 patients who had received adjuvant tamoxifen, high AIB1 expression was associated with poorer prognosis and shorter disease-free survival (DFS).

ERBB2 signalling through MAPK (mitogen-activated protein kinase) activates both the ER and AIB1, and some studies have indicated that high ERBB2 expression is associated with tamoxifen resistance, so do ERBB2 and AIB1 interact to affect the response of a tumour to tamoxifen? The authors found that untreated patients with high ERBB2, regardless of level of expression of AIB1, had worse prognosis than those with low ERBB2. However, high ERBB2 plus high AIB1 in patients who had received adjuvant tamoxifen was an even worse prognostic factor. DFS in these patients was 42% versus 70% in patients with any other combination of ERBB2 and AIB1 expression.

So, these results confirm laboratory findings that ER co-activators can enhance the ER agonist activity of tamoxifen — the drug is less effective in patients with high AIB1 levels. The role of AIB1 in tamoxifen resistance might explain why correlations in previous studies in which only ERBB2 was measured in tamoxifen-treated patients have been inconsistent.