SIVA1 Knockdown Drives Aggressive Phenotypes in Triple-Negative Breast Cancer Cells while Enhancing Paclitaxel Efficacy.

SIVA1 is a multifunctional protein involved in processes that are critical for tumor progression. In breast cancer, SIVA1 is frequently overexpressed; however, its functional role remains poorly defined. This study aimed to elucidate the cellular mechanisms regulated by SIVA1 and to characterize its molecular network in breast cancer. Integrated in silico analyses and in vitro functional and molecular assays in breast cancer cell lines were conducted to investigate SIVA1 expression and associated signaling pathways. Cell proliferation, migration, invasion, and drug sensitivity were assessed in 2D and 3D culture models. Molecular analyses included markers of DNA damage and apoptosis, cytoskeletal regulators, ubiquitination status, and p53 signaling. The subcellular localization of SIVA1 was investigated. SIVA1 was overexpressed in breast cancer cells and associated with pathways related to protein secretion, spliceosome activity, DNA repair, and oxidative stress. Functional analyses linked SIVA1 to mitochondrial permeabilization, ubiquitin-mediated processes, cytoskeletal regulation, and p53-dependent apoptosis. SIVA1 knockdown increased cell growth, migration, and invasion, while enhancing sensitivity to paclitaxel in both 2D and 3D models, evidenced by reduced ATP levels and increased cleaved PARP1 and γ-H2AX. SIVA1 knockdown resulted in the accumulation of phosphorylated p53 and reduced phospho-Stathmin 1 and ubiquitin levels. SIVA1 displayed predominant nuclear localization, independent of treatment. In summary, these findings identify SIVA1 as a key regulator of proliferation and cytoskeletal dynamics in breast cancer, whose inhibition induces a more aggressive yet taxane-sensitive phenotype, with potential implications for patient stratification and therapeutic decision-making.