We have developed a
breast cancer intratumoral
aromatase model to simulate the postmenopausal
breast cancer patient in order to compare the antitumor efficacy of
aromatase inhibitors (AIs) and
antiestrogens (AEs). The AI
letrozole sustained growth inhibition longer than the AE
tamoxifen. Nevertheless, eventually
tumors began to grow despite continued treatment.
Estrogen receptor-alpha (ER-alpha) levels decreased below control levels concomitant with increased phosphorylation of ER-alpha and unaltered
progesterone receptor (PgR) levels. Expression of Her-2, p-Shc, Grb-2, p-Raf, p-Mekl/2, and p-MAPK was increased in the
letrozole-resistant
tumors. When cells isolated from
letrozole-resistant
tumors (LTLTCa cells) were treated with inhibitors of the Her-2 signaling pathway, such as
trastuzumab (
herceptin), ER-alpha was restored. Furthermore, sensitivity of LTLTCa cells to AIs and AEs was regained. These findings suggest cross-talk between ER and Her-2 signaling. To prevent activation of the Her-2 pathway and resistance to AIs, mice were treated with a combination of an AI
anastrozole and the ER downregulator
fulvestrant. This resulted in no increase in Her-2 and p-MAPK levels, and
tumor growth was significantly inhibited. Thus, blocking both ER and Her-2 signaling delayed development of resistance to AIs. This hypothesis was supported by the finding that growth of
letrozole-resistant
tumors was reduced when xenografts were treated with
trastuzumab combined with
letrozole. In addition, resistance to
letrozole could be reversed by discontinuing
letrozole. Our findings indicate that after
letrozole treatment is stopped, the antitumor effect of
letrozole can be restored when the AI treatment is resumed.