Abstract Inflammatory Breast Cancer (IBC), an aggressive and rare form of breast cancer, is characterized byhigh metastatic potential and an inflammatory microenvironment. The Myristoylated Alanine-Rich CKinase Substrate (MARCKS) protein is overexpressed in IBC, suggesting its involvement in theinflammatory activation linked to its aggressiveness. Our study explored the role of MARCKS andinflammatory signaling pathways in IBC, using both in vitro (siRNA-mediated inhibitionof MARCKS in SUM149, KPL4 and MDA-MB-231 cell lines) and in silico (differential geneexpression analysis, annotation, enrichment, identification and visualization of pathways containingthese genes) approaches. Our in vitro studies showed that the inhibition of MARCKS reducedmigration and pro-tumor activity of IBC cells vs. non-inflammatory breast cancer (nIBC) underinflammatory conditions following treatment with lipopolysaccharide (LPS). Furthermore, mRNAexpression analysis by qRT-PCR, NFkBIB and NFkBIE expression were upregulated followingMARCKS inhibition by siRNA and this only in IBC compared to non-IBC. Interestingly, for NF-κB-IE, a significant decrease and increase in expression was observed after transfection in all three ISCmodel lines compared to ISC. In KPL4 cells, expression increased from approximately 0.03419 to1.376 units (p = 0.007). In the SUM149 cell line, this increase was even more pronounced withexpression increasing from 0.8194 to 1.801 units (p 0.001), while in MDA-MB-231 cells, it alsodecreased from -0.9488 to -0.4712 units (p = 0.007). We also assessed protein expression ofMARCKS and NFκB in a series of 40 samples from patients with IBC. Our results showed thatoverexpression of NFκB, a major transcription factor in chronic inflammation, was associated withthat of MARCKS in IBC patients (p = 0.003). In silico, we demonstrated different alterations in keypathways (PI3K/AKT, JAK/STAT) involved in inflammation and cell proliferation. These resultsconfirm the importance of MARCKS in IBC tumor inflammation and open up prospects for itspersonalized therapeutic targeting.Keywords: Inflammatory breast cancer, inflammation, MARCKS, signaling pathways Citation Format: M. Manai, N. Boughzala, N. Bayou, P. Finetti, N. Akkari, O. Bejar, M. Selmi, Y. Houcine, R. Benhassen, C. Reduzzi, J. Donahue, V. Fraser, E. Nicolò, M. Driss, F. Bertucci, H. Boussen, M. Cristofanilli. The role of MARCKS in inflammation in inflammatory breast cancer using in vitro and in silico studies 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 PS2-12-18.
Manai et al. (Tue,) studied this question.