Trastuzumab Reverses Letrozole Resistance and Amplifies the Sensitivity of Breast Cancer Cells to Estrogen

In this study, we investigated adaptive mechanisms associated with aromatase inhibitor (AI) resistance in breast cancer cells and show that sensitivity to AIs can be extended through dual inhibition of estrogen receptor (ER) and human epidermal receptor-2 (Her-2) signaling. We used human ER-positive breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). These cells grow as tumors in nude mice and are inhibited by AIs. Despite continued treatment, tumors eventually become insensitive to AI letrozole. The cells isolated from these long-term letrozole-treated tumors (LTLT-Ca) were found to have decreased ER alpha levels. Our results suggest that LTLT-Ca cells survive estrogen deprivation by activation of Her-2/mitogen-activated protein kinase (MAPK) pathway. Here, we show that trastuzumab (antibody against Her-2; IC50 = 0.4 mg/mL) was very effective in restoring the ER alpha levels and sensitivity of LTLT-Ca cells to endocrine therapy by down-regulation of Her-2/MAPK pat way and up-regulation of ER alpha. In contrast, trastuzumab was ineffective in the parental hormone-responsive MCF-7Ca cells (IC50 = 4.28 mg/mL) and xenografts. By blocking Her-2, trastuzumab also up-regulates ER alpha and aromatase expression and hypersensitized MCF-7Ca cells to E-2. We show that trastuzumab is beneficial in hormone-refractory cells and xenografts by restoring ER, implicating Her-2 as a negative regulator of ER alpha.. In xenograft studies, the combination of trastuzumab plus letrozole is equally effective in inhibiting growth of MCF-7Ca tumors as letrozole alone. However, on the acquisition of resistance and increased Her-2 expression, the combination of letrozole plus trastuzumab provided superior benefit over letrozole or trastuzumab alone. [Cancer Res 2009;69(4):1416-28]