Understanding resistance to endocrine agents: molecular mechanisms and potential for intervention.

BACKGROUND: We developed a mouse model system that mimics hormone-dependent postmenopausal breast cancer. In this model, human estrogen receptor-positive (ER+) breast cancer cells (MCF-7) stably transfected with aromatase (MCF-7Ca) are grown as tumors in ovariectomized female nude mice. Using this model, we have established that aromatase inhibitors (AIs) such as letrozole and anastrozole that reduce estrogen production are more effective than the antiestrogen agent tamoxifen. This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. Nevertheless, resistance to treatment might eventually occur.

MATERIALS AND METHODS: To investigate the mechanisms involved in the loss of sensitivity of the tumors to AIs, we developed a cell line isolated from the tumors of long-term letrozole-treated MCF-7Ca xenografts. This cell line was designated LTLT-Ca.

RESULTS: These cells exhibited lower expression of ERalpha and apparent "estradiol-independent" growth along with hyperactivation of growth factor receptor- mediated signaling pathways such as HER2/mitogen-activated protein kinase. The inhibition of HER2 with trastuzumab results in restoration of ERalpha and response to letrozole.

CONCLUSION: Our data suggest that inhibition of both the HER2 and estrogen signaling pathways is required to prolong the responsiveness of the tumors to endocrine therapies. In addition, we have shown that HER2 upregulation is an adaptive process that the tumors undergo during continued letrozole treatment, which is reversed upon removal of the treatment. The tumors regain responsiveness to letrozole after a short period "off" treatment. These studies suggest that by reversing the resistance to hormone therapy, patients could have a second response and could delay the need for chemotherapy.