Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response.

Endocrine therapy, and especially tamoxifen, is the most important systemic treatment of estrogen receptor (ER)-positive breast cancer at all stages. A serious obstacle, however, is intrinsic or acquired resistance to these therapies, which in the case of selective ER modulators, such as tamoxifen, involves some imbalance of their agonist versus antagonist actions. Recent data suggest that levels of both ER coregulatory proteins and extra and intracellular signaling from growth factor-related pathways may be important in adjusting this mixed agonist/antagonist activity of selective ER modulators in resistant breast tumors. We suggest that ER coregulators' mediation of growth factor and other cellular signaling to the ER pathway is an important feature in endocrine response and resistance in breast cancer. Indeed, we find that failure of the antitumor activity of tamoxifen in patients with breast cancer is actually determined by both the levels of and the interaction between the ER coactivator amplified in breast cancer-1 (AIB1) and the epidermal growth factor-related protein HER. Thus, the interactions of these diverse elements are essential considerations in defining new predictive and therapeutic tools.