Abstract PS3-12-13: Adipocyte-tumor cell interactions drive aggressiveness in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, representing approximately 10-20% of all cases. It is distinguished by a unique tumor microenvironment in which immune components play a critical prognostic role. Beyond immune cells, various stromal elements contribute to cancer progression, with tumor cells actively shaping their microenvironment through bidirectional interactions that influence the recruitment and functional phenotype of these surrounding cells. Among stromal components, adipocytes—the predominant stromal cells in breast tissue—have gained increasing attention. This study aimed to determine whether interactions between TNBC cells and adipocytes promote cancer aggressiveness. At the cellular level, we found that the interaction between tumor cells (MDA-MD-231, SUM149PT, HCC1937, BT549 and MDA-MB-468) and mature adipocytes—derived from differentiation of ASC52 mesenchymal stem cells—induces adipocyte delipidation, marked by a reduction in both the number and size of lipid droplets and a significant decrease in overall lipid content compared to control adipocytes, as quantified by Oil red O staining. This phenotypic shift is accompanied by a marked downregulation of mature adipocyte markers, including PPARG, CEBPA, and ADIPOQ, as well as reduced PPARG transcriptional activity, evidenced by decreased expression of FABP4. Furthermore, these adipocytes exhibit a distinct transcriptional profile enriched in inflammatory pathways and genes involved in tumor microenvironment interactions. Tumor cells exposed to adipocytes acquire features of epithelial-mesenchymal transition and cancer stemness, as demonstrated by qPCR analysis of specific markers and flow cytometry. In patients, we defined an adipose tissue infiltration (ATi) score, defined as involvement of ≥10% of the tumor margin (ATi-positive), reflecting interaction between tumor cells and adipocytes. In a cohort of 92 consecutive patients with primary TNBC who underwent surgery and received adjuvant chemotherapy, the ATi score was associated with a higher relapse rate (p=0.0152), lower tumor-infiltrating lymphocytes (TILs), and older age. Notably, ATi-positive status was significantly associated with poorer disease-free survival (DFS) (HR=3.13; 95% CI: 1.16-8.50). This association was independent of other clinico-pathological factors including age, tumor size, lymph node involvement, and TILs in multivariate analysis, supporting the role of tumor-AT crosstalk in TNBC progression. Collectively, our findings strongly indicate that the interaction between tumor cells and adipocytes contributes to the aggressiveness of TNBC, underscoring the importance of further investigating the underlying mechanisms for potential therapeutic targeting. Supported by Fondazione AIRC Citation Format: T. Triulzi, M. Francesconi, S. Iannicelli, V. Regondi, L. De Cecco, E. Tagliabue, S. M. Pupa, A. Vingiani. Adipocyte-tumor cell interactions drive aggressiveness in triple-negative breast cancer [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 PS3-12-13.