FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Mutations in the pioneer transcription factor FOXA1 are frequently observed in estrogen receptor-positive (ER+) breast cancers.
• FOXA1 plays a crucial role in regulating gene expression in breast cancer development and progression.

Purpose of the Study:

• To investigate the functional impact of FOXA1 mutations found in breast cancer patients.
• To understand the mechanistic basis for altered FOXA1 function and its association with therapeutic response.

Main Methods:

• Analysis of FOXA1 mutations in a large cohort of breast cancer patients (∼5,000).
• Utilized breast cancer models and a clinico-genomically curated cohort.
• Employed chromatin binding assays, transcription assays, structural modeling, and transcriptomic analysis.

Main Results:

• Identified hotspot mutations in the Wing2 region and a specific mutation SY242CS.
• FOXA1 mutations were associated with a reduced response to aromatase inhibitors.
• Wing2 mutations enhanced ER-mediated transcription, while SY242CS exhibited neomorphic properties, opening new chromatin regions and altering gene expression.
• SY242CS mutation predicted to cause conformational changes enabling binding to non-canonical DNA motifs.

Conclusions:

• FOXA1 mutations significantly impact its function, influencing chromatin binding and transcriptional activity.
• Specific FOXA1 mutations can lead to altered therapeutic responses in ER+ breast cancer.
• Understanding these mutations provides insights into breast cancer progression and potential therapeutic strategies.