A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells

Abstract

Estrogen receptor ␣ (ER␣)3 is a member of the steroid/nuclear receptor family of transcription regulators and mediates cell growth and metastasis and resistance to apoptosis and immunosurveillance (1-5). ER␣ is activated by binding of 17␤-estradiol (E 2 ), or by the epidermal growth factor-activated extracellular signal-regulated kinase pathway and other signal transduction pathways (6). ER␣-mediated gene transcription contributes to the development and spread of breast, uterine, and liver cancer (5,7,8). A role for ER action in ovarian cancer is supported by the recent finding that endocrine therapy is effective against relapsed ER-containing ovarian cancers (9, 10). Aromatase inhibitors that inhibit estrogen production and tamoxifen (Tam) and other selective estrogen receptor modulators (SERMs) are mainstays in treatment of estrogen-dependent cancers and have played an important role in developing our understanding of ER action (5,7,11,12). Tam and other SERMs work by competing with estrogens for binding in the ligand binding pocket of ER. Over time, tumors usually become resistant to tamoxifen and other SERMs (13-15), requiring new strategies to inhibit ER␣ action.In the best characterized model for ER action, ER␣ activates gene transcription by binding to palindromic estrogen response element (ERE) DNA and ERE half sites (4,16, 17). Thus, an alternative to current approaches that primarily target ER action at the level of ligand binding is to target ER␣ at the level of its interaction with ERE DNA. Although targeting protein binding to DNA is attractive, until recently this approach was questioned, because small molecules may not disrupt the large interaction surfaces of protein⅐DNA and protein⅐protein complexes (18). However, several recent studies support the feasi-

Designer Monotransregulators Provide a Basis for a Transcriptional Therapy for De Novo Endocrine-Resistant Breast Cancer

“…Studies have shown that prevention of ER binding to ERE sequences of responsive genes by exogenously introduced ERE decoys (21) or electrophilic agents that disrupt zinc-fingers of ERα (22)(23)(24) represses E2-mediated growth of ERpositive breast cancer cells. Complementing this, we recently reported that genomic responses from the ERE-dependent pathway mediated by E2-ER are required to suppress the growth of ER-negative cells as well (10,11).…”

“…Since ER plays a pivotal role in both the initial response and subsequent resistance to antiestrogenic compounds, additional therapeutic benefits could be achieved by preventing ER synthesis or function. Repression of ER synthesis by inhibitory RNA technologies (43) or interference with endogenous ER functions by future generations of antiestrogenic compounds (44) or ERspecific electrophilic agents (22)(23)(24) could constitute strategies for the treatment of acquired endocrine-resistant breast cancers. Since these approaches target ER, however, circumvention of ER-dependent events by growth signaling pathways could lead to tumor progression.…”

Regulation of Estrogen Receptor-mediated Long Range Transcription via Evolutionarily Conserved Distal Response Elements

“…To explore in further detail whether direct binding of ER␣ to the EREs in the distal and proximal ER binding sites is necessary for chromosome interaction, we specifically blocked ER␣ from binding to DNA with TPBM, a newly identified small molecular inhibitor that binds to the DNA binding domain of ER␣ (18). As shown in Fig.…”

A Competitive Inhibitor That Reduces Recruitment of Androgen Receptor to Androgen-responsive Genes

“…An effective small molecule inhibitor of AR should exhibit high potency and specificity. Our studies show that CPIC inhibits AR transcriptional activity, with little or no effect on GR or ER␣ under the same conditions where other small molecules robustly inhibited ER␣ and GR (26,48). CPIC effectively inhib-FIGURE 10.…”