Mounting evidence implicates Protein Kinase C-δ (PKC-δ) in breast cancer progression and therapy resistance. PKC-δ is activated by the second messenger diacylglycerol or by proteolytic cleavage, both of which expose the kinase's catalytic site and allow substrate phosphorylation. Furthermore, the C2 domain of PKC-δ regulates the kinase by mediating intra and intermolecular protein-protein interactions. Here, we investigated the autonomous effects of the PKC-δ C2 domain in two breast cancer cell lines, representing hormone-dependent and triple-negative breast cancer. A myc-tagged PKC-δ C2 domain (myc-δC2) was stably overexpressed in MCF-7 and MDA-MB-468 cells, and its effects on cell viability, apoptosis, and proliferation were assessed. myc-δC2 expression reduced cell viability and increased apoptosis in both cell lines. In MCF-7 cells, but not in MDA-MB-468 cells, G2/M arrest and increased cell size were observed upon myc-δC2 expression. Under oxidative (H₂O₂) and genotoxic (etoposide) stress, myc-δC2 expression sensitized cells differently in the two cell lines: MCF-7 cells showed consistent sensitization, whereas in MDA-MB-468 cells, sensitization was observed only at higher stress levels or after dasatinib pretreatment. These results indicate a cell line-dependent pro-death role for the isolated PKC-δ C2 domain, highlighting that modulation of this domain, or its use as an autonomous pro-apoptotic agent, may offer new therapeutic avenues in breast cancer.