Abstract
Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10–40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERα proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ERα LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ERα. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.
Highlights
Since Y537S, D538G, and ESR1-YAP1 ERα (Fig. 1a) promote E2-independent transcriptional activation of an estrogen response element (ERE)-dependent reporter (Fig. 1b), we tested whether this activation is through recruiting or repelling distinct coregulators
Consistent with prior literature [7, 9, 14, 18, 19, 55, 56], steroid receptor coactivators (SRCs) display enhanced recruitment to EREs bound by the two ligand-binding domain (LBD) ERα mutants as compared with unliganded WT ERα
Since all three SRCs are recruited to the two LBD ERα mutants, therapeutic intervention likely must be directed toward all three proteins
Summary
75% of breast cancers express estrogen receptor alpha (ERα) and new therapies are needed for the ~50% of ER-positive tumors that acquire endocrine resistance [1]. 10 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
