Aromatase resistance mechanisms in model systems in vivo.

Aromatase inhibitors (AIs) have now been shown to be more effective than the anti-estrogen (AE) tamoxifen and have few side effects in ER+ breast cancer patients. However, some patients may not respond and resistance to treatment may develop in others. To investigate the mechanisms involved in the loss of sensitivity of the tumors to AIs, we have studied athymic mice with tumors grown from human estrogen receptor (ER) positive breast cancer cells (MCF-7) stably transfected with aromatase (MCF-7Ca). Treatment with letrozole upregulated Her-2 after four weeks despite continued responsiveness of tumor growth to letrozole. Furthermore, the level of Her-2 protein in letrozole refractory tumors was found to be six fold higher than the control tumors. Cells isolated from these tumors also had increased levels of Her-2 along with lower expression of ERalpha and aromatase and apparent estradiol independent growth. When Her-2 was inhibited by trastuzumab (antibody against Her-2) ERalpha levels in the cells were restored indicating that Her-2 is a negative regulator of ERalpha. This interaction between Her-2 and ER suggests that inhibition of both the Her-2 and estrogen signaling pathways is required to prolong the responsiveness of the tumors to endocrine therapies. Thus, when treatment with trastuzumab and letrozole was combined, ER was restored and tumor growth markedly inhibited compared to treatment with either drug alone. These findings demonstrate that tumor cells under the stress of treatment can adapt and utilize alternate pathways. Thus, when letrozole treatment was stopped, tumor Her-2 levels declined and ER levels were restored to those of hormone sensitive tumors. A second course of letrozole treatment inhibited tumors growth to the same extent and for as long as the initial treatment. These and other strategies to restore aromatase and ERalpha resulting in sensitivity to hormone therapy could be of substantial benefit to patients who have acquired resistance to AIs.