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.