The molecular mechanisms underlying the pharmacological actions of ER modulators: implications for new drug discovery in breast cancer

Abstract

Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the Selective Estrogen Receptor Modulators (SERMs) tamoxifen and raloxifene, so called for their ability to function as ER agonists or antagonists depending on the tissue in which they operate. These mechanistic insights have had a significant impact on the discovery of second generation SERMs, some of which are in late stage clinical development for the treatment/prevention of breast cancer as well as other estrogenopathies. In addition to the SERMs, however, have emerged the Selective Estrogen Degraders (SERDs), which as their name suggests, interact with and facilitate ER turnover in cells. One drug of this class, fulvestrant, has been approved as a third line treatment for ER-positive metastatic breast cancer. Whereas the first generation SERMs/SERDs were discovered in a serendipitous manner, this review will highlight how our understanding of the molecular pharmacology of ER ligands has been utilized in the development of the next generation of SERMs/SERDs, some of which are likely to have a major impact on the pharmacotherapy of breast cancer.

Figure 1. The physical and functional interaction between the ER and Her2/IGFR signaling pathways in breast cancer cells influences the pharmacology of ER ligands

The transcriptional activity of ERα and its pharmacological response to endogenous and exogenous ligands is determined in large part by the repertoire of coregulators expressed in a given cell and the impact of activated signaling pathways on the activity of receptor:coregulator complexes. Whereas there are a large number of coregulators, each of which may have a different effect on receptor activity, a model highlighting the interactions between the ERα-SRC-3/Her2 regulatory axis is presented for illustrative purposes. The complete details supporting this model are presented in the text. In short, however, it is now clear that differences in SRC-3 expression or activity can result in differential activation of the ER target genes. Of particular importance is the observation that increases in SRC-3 activity and or expression can relieve ER-mediated repression of Her2 expression. This initiates a positive feed forward loop that results in increased Her2 signaling and subsequently increased ER signaling. Under these conditions the biocharacter of tamoxifen has been shown to switch from that of an antagonist to an agonist.

Figure 2. Understanding the role of coregulators in ER action in breast tumors is instructive with respect to new drug development

Upon binding tamoxifen ERα adopts a conformation that is distinct from apo-ERα and that which occurs upon binding estradiol. This conformational change disrupts the primary coregulator binding surface on ERα and reduces the affinity of the receptor for coregulators. Consequently, in cells where coregulators are not overexpressed or hyperactivated, tamoxifen is capable of inhibiting ER action. However, under the selective pressure of tamoxifen administration, something changes within the cell that alters the coactivator milieu such that the tamoxifen:ER complex can engage a coregulator that allows it to activate transcription. This could result from (a) the overexpression of a cofactor with which the receptor normally interacts when occupied by estradiol or (b) the expression of a cofactor that can interact in an ectopic manner with the receptor:tamoxifen complex. The ability of compounds that enable ERα to adopt a unique conformation to effectively inhibit the growth of tamoxifen resistant tumors highlights the validity of this model. It should also be apparent from this discussion why there is so much interest in developing SERDs that function by completely removing the possibility of “productive” ER-coregulator interactions.