Adaptive Changes Result in Activation of Alternate Signaling Pathways and Acquisition of Resistance to Aromatase Inhibitors

Hormone therapy is an effective approach for the treatment of breast cancer. Although the antiestrogen tamoxifen has had a major impact on the treatment of the disease, aromatase inhibitors (AIs), which reduce estrogen synthesis, have recently proved to be more effective. These agents are now used as first-line therapy for postmenopausal breast cancer. Nevertheless, despite the efficacy of these agents, resistance to treatment eventually may occur in some patients. In an effort to overcome this resistance and extend the benefits of AIs, investigators have studied the mechanisms involved in resistance to AIs. Adaptive changes that result in activation of alternate signaling pathways in AI-resistant tumors have been identified in xenograft and cell line models. Expression of estrogen receptor a and aromatase was shown to be decreased in tumors after long-term treatment with AIs. In contrast, increased expression was observed in tyrosine kinase receptors such as Her-2 and insulin-like growth factor receptor, as well as in downstream signaling proteins such as mitogen-activated protein kinase. Functional activation of the mitogen-activated protein kinase pathway and dependency on growth factor receptor signaling have been observed in AI-resistant cells and tumors. Clin Cancer Res; 17(13); 4208-13. (C) 2011 AACR.