Adaptive changes results in activation of alternate signaling pathways and resistance to aromatase inhibitor resistance

Hormone therapy is an effective approach for the treatment of breast cancer. The antiestrogen tamoxifen has had a major impact on the disease. Recently, aromatase inhibitors which reduce estrogen synthesis have proved to be more effective and these agents are now used as first line therapy for postmenopausal breast cancer. Nevertheless, resistance to treatment eventually may occur. We have investigated mechanisms involved in resistance to AIs and devised strategies to overcome the resistance. Using a xenograft model, we have identified adaptive changes that results in activation of alternate signaling pathways in tumors resistant to aromatase inhibitors. Expression of ERα and aromatase was decreased in the tumors after long term treatment with AIs. In contrast increased expression was observed of tyrosine kinase receptors such as HER-2 and IGFR as well as of downstream signaling proteins, including MAPK. We have demonstrated functional activation of the MAPKinase pathway and shown dependency on growth factor receptor signaling in letrozole resistant cells. Furthermore, our studies indicate that HER-2 is a negative regulator of ER. Thus, when HER-2 was blocked with antibody (herceptin, trastuzumab) ER expression was increased rendering the cells and tumors responsive to aromatase inhibitors and resulting in tumor regression.