Abstract 3226: FOXA1 alterations drive endocrine therapy resistance through unique transcriptional and epigenomic programs in breast cancer

Abstract Breast cancer is histologically classified into invasive ductal carcinoma (IDC, ∼70-80% of cases) and invasive lobular carcinoma (ILC, 10-15%). Both are predominantly estrogen receptor-positive (ER+) and treated with endocrine therapy, yet resistance inevitably develops, driving metastasis and poor outcomes. ILC exhibits hallmark E-cadherin loss, distinct metastatic patterns, and reduced endocrine therapy response compared with stage-matched IDC. However, treatment remains uniform across histologies, underscoring the need to define shared and subtype-specific drivers of resistance. Clinicogenomic analyses of 8,500 MSK-IMPACT tumors revealed recurrent FOXA1 mutations in ER+ disease, enriched in ILC (8% vs 4% in IDC). As a pioneer transcription factor that licenses ER chromatin binding, FOXA1 alterations may reshape ER signaling to promote therapy resistance. To investigate this, we functionally characterized recurrent FOXA1 Helix 1 (H1), Wing2 (W2), and betastrand3 (S3) mutations in IDC (MCF7, T47D), and H1, W2 variants in ILC (MDA-MB-134VI). We assessed treatment response under estrogen deprivation, fulvestrant or oral SERDs ± CDK4/6i and profiled transcriptional and chromatin changes using RNA-seq, ER CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3226.