The aromatase inhibitor letrozole enhances the effect of doxorubicin and docetaxel in an MCF7 cell line model

Introduction: Post-menopausal women with estrogen receptor (ER) positive breast cancer receive adjuvant chemotherapy and endocrine therapy sequentially since tamoxifen may antagonise the cytotoxicity of chemotherapy drugs. With increased use of aromatase inhibitors (AIs) in place of tamoxifen, the potential use of concomitant chemo-endocrine treatments with the AI letrozole, before clinical trials are undertaken, requires evaluation. Methods: MCF7-aro cells expressing the aromatase gene were treated with letrozole, doxorubicin and docetaxel. The effects of different drug concentrations, drug combinations and scheduling on cytotoxicity and aromatase activity were investigated. Key receptor, cell cycle regulation and apoptosis proteins were examined by immunoblotting. Results: Administration of letrozole with either doxorubicin or docetaxel resulted in increased levels of cytotoxicity under all treatment schedules (add in, sequential or simultaneous drug administration) with the greatest anti-proliferative effect observed using concomitant treatment (letrozole first with chemotherapy added in). The inhibitory effect of letrozole on aromatase activity was unchanged by the addition of doxorubicin or docetaxel. Letrozole treatment resulted in decreased HER2 expression and addition of doxorubicin and docetaxel to letrozole led to elevated ER-ß levels. Conclusions: In vitro, letrozole, unlike tamoxifen, enhances the cytotoxicity of both doxorubicin and docetaxel. This supports the prospect of trials using letrozole with chemotherapy in postmenopausal women with ER positive breast cancer