Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets
Leah A Gates1,2, Guowei Gu1,3, Yue Chen4
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
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.
Insights
Identifying coactivators for estrogen receptor alpha (ERα) mutants is key for treating endocrine-resistant breast cancer. Targeting these coactivators may offer new therapeutic strategies for patients with resistant disease.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Estrogen receptor alpha (ERα)-positive breast cancers (approx. 75%) are treated with endocrine therapies.
- Resistance to endocrine therapy is a major challenge, often driven by mutations in the ESR1 gene.
- ESR1 mutations lead to ligand-independent ERα activity or fusion proteins unresponsive to treatment.
Purpose of the Study:
- To identify coactivators that interact with common ERα mutants.
- To explore potential therapeutic targets for endocrine-resistant breast cancer.
Main Methods:
- Proteomics approach to profile proteins recruited to ERα mutants (Y537S, D538G) and an ESR1-YAP1 fusion protein.
- Assessed coactivator interactions with wild-type ERα versus mutants.
- Investigated the effect of coactivator inhibition on mutant ERα activity and cancer growth.
Main Results:
- ERα mutants (Y537S, D538G, ESR1-YAP1) showed increased coactivator interactions compared to unliganded wild-type ERα.
- Inhibiting identified coactivators reduced mutant ERα-mediated transcription activation.
- Coactivator inhibition suppressed breast cancer growth in vitro and in vivo.
Conclusions:
- Specific coactivators are recruited to mutant ERα proteins.
- These coactivators represent potential therapeutic targets for endocrine-resistant breast cancers.
- Targeting coactivators may overcome resistance to endocrine therapies.
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