Nuclear and cytoplasmic expressions of ERβ1 and ERβ2 are predictive of response to therapy and alters prognosis in familial breast cancers

Estrogen receptor (ER) alpha has been studied extensively in familial breast cancers but there are limited data on ER beta and its isoforms. This is an important issue since many BRCA1-associated tumours are "triple negative" and are resistant to conventional and targeted therapies. We performed an immunohistochemical study of pan-ER beta, ER beta 1 and ER beta 2 in a cohort of 123 familial breast carcinomas (35 BRCA1, 33 BRCA2 and 55 BRCAX) using a cut-off for positivity at 20% (Shaaban et al. in Clin Cancer Res 14:5228-5235, 2008). BRCA1 cancers were more likely to be nuclear ER alpha negative and nuclear pan-ER beta positive (21/32, 66%) when compared with BRCA2 (2/29, 7%) and BRCAX cancers (11/49, 22%) (both P < 0.001). For survival analysis, expression was also stratified using cut-offs defined by Bates et al. (Breast Cancer Res Treat 111:453-459, 2008) (score out of 7). Cytoplasmic ER beta 2 expression correlated with shorter overall survival at 15 years regardless of cut-off used (both P < 0.046) At a cut-off score of 6 out of 7, cytoplasmic ER beta 2 expression correlated with a poorer response to chemotherapy in both univariate (P = 0.011) and multivariate analyses including grade, lymph node status and chemotherapy as an interaction variable (P = 0.045, Hazard ratio 1.22, 95% CI 1.004-9.87). A similar trend was seen in a univariate analysis with a cut-off of 20% although this did not reach statistical significance (P = 0.057). Expression of nuclear ER beta 1 was associated with a favourable response to endocrine therapy at 15 years regardless of cut-offs employed (both P < 0.025). However, this did not reach statistical significance in a multivariate analysis (P > 0.05). Since a significant proportion of ER alpha negative familial breast carcinomas are positive for nuclear ER beta 1 and cytoplasmic ER beta 2, the different ER beta isoforms and their intracellular location may need to be assessed, to identify patients that may benefit from hormonal and chemotherapy.