Abstract Background: Invasive lobular carcinoma (ILC) accounts for 10-15 % of breast cancers and is linked to poorer long-term survival than invasive carcinoma of no special type (NST), yet current therapy remains identical to stage matched NST regimens. Seeking ILC-specific vulnerabilities and targets, we have recently identified the transcription factor AP-2β (TFAP2B) as one of the most hypomethylated genes in ILC relative to NST and normal breast tissue. Concordantly, TCGA, METABRIC and SCAN-B datasets show significant TFAP2B upregulation in ILC, with hypomethylation of the first-exon CpG island showing the strongest correlation with mRNA expression. Clinically, high TFAP2B expression is associated with worse survival in patients with ILC in the METABRIC dataset, further supporting its potential role in disease progression. Therefore, the current study aimed to elucidate the ILC-specific role of and dependency on TFAP2B and to assess its potential as a therapeutic target. Methodology: TFAP2B mRNA and protein expression as well as DNA methylation levels were assessed across breast-cancer cell lines, patient-derived organoids (PDOs), and tumor samples. Functional roles of TFAP2B were tested by siRNA or inducible shRNA knockdown in ER-positive and ER-negative ILC cell lines (including MDA-MB-134 and MDA-MB-453) and by inducible TFAP2B over-expression in NST models (MCF7, T47D, and MDA-MB-231), followed by assays for anchorage-dependent and independent growth, colony formation, soft agar growth, cell-cycle analyses and apoptotic cell death. To assess regulation by E-cadherin, TFAP2B expression was evaluated after CDH1 knockout or inducible CDH1 expression in NST and ILC models, respectively. Preliminary mechanistic insights were obtained through CUT-RUN, RNA-seq and reverse-phase protein arrays following TFAP2B knockdown or overexpression. Results and conclusions: TFAP2B exhibited selective upregulation with uniform nuclear localization in ILC cell lines, PDOs and tumors. Knocking down TFAP2B markedly impaired ILC proliferation in both anchorage-dependent and independent contexts, suppressed colony formation and soft agar growth, reduced S-phase entry and EdU incorporation, expanded the G0-G1 population, lowered the anti-apoptotic protein BCL2 and increased apoptotic cell death. Conversely, inducible TFAP2B over-expression in NST cells hindered proliferation and blocked the G1 to S phase transition. Altering E-cadherin levels did not affect TFAP2B levels, indicating independence from CDH1 status in the transformed cells. Preliminary CUT-RUN, and transcriptomic data point to TFAP2B regulation of cell-cycle, chromatin-remodeling and metabolic pathways. Further studies are ongoing to uncover downstream targets, pathways and interaction partners specific to TFAP2B in ILC. Collectively, the data establish TFAP2B as an ILC specific driver that promotes proliferation and survival and is associated with adverse clinical outcomes. Functional dependence of ILC but not NST cells on TFAP2B underscores its promise as a therapeutic target uniquely tailored to lobular breast cancer. Citation Format: A. Wedn, H. Waltermire, F. Chen, C. Merkel, D. Brown, O. Shah, J. Hooda, R. Bhargava, A. Lee, S. Oesterreich. Epigenetic upregulation of TFAP2B expression drives proliferation and survival in Invasive Lobular Carcinoma abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD9-02.
Wedn et al. (Tue,) studied this question.