Differential effects of aromatase inhibitors and antiestrogens on estrogen receptor expression in breast cancer cells

Background: Estrogen receptors (ER) α and β play an important role in breast cancer. Recently, systemic adjuvant endocrine therapy with selective estrogen receptor modulator (SERM) tamoxifen has been challenged by aromatase inhibitors. Compared to antiestrogens, third-generation aromatase inhibitors (anastrozole and letrozole) exhibit an improved efficacy and tolerability. Materials and Methods: Using real-time PCR analysis, 21 breast cancer tissue samples were analysed for a change of the ERα/ERβ ratio during malignant progression. In stimulation experiments, differential effects of SERMs, ER antagonists and aromatase inhibitors have been investigated. Results: Transition from normal breast to grade 1 tumors was characterized by down-regulation of ERβ (relative quantification [RQ]=0.83, p=0.019), while transition from grade 1 to grade 3 tumors was associated with the decrease of ERα expression (RQ=1.14 vs. RQ=0.65, p<0.001). In stimulation assays, tamoxifen and fulvestrant increased ERα expression to RQ=1.51 (p=0.01) and RQ=1.42 (p<0.001), respectively, and left ERβ unchanged. In contrast, aromatase inhibitors up-regulated ERβ to RQ=1.23 (anastrozole, p=0.029) and RQ=1.38 (letrozole, p=0.048). Conclusion: Taken together, data indicate that SERMs/antiestrogens and aromatase inhibitors exhibit opposed effects on the ER expression of breast cancer cells: tamoxifen and fulvestrant up-regulate ERα expression, while aromatase inhibitors increase ERβ expression, which may contribute to the aromatase inhibitors' therapeutic superiority over antiestrogens.