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Simple Summary: Globally, breast cancer is the most common malignancy and the most frequent cause of cancer-related deaths among women. Chemotherapy is the major systemic treatment for breast cancer, but unfortunately patients often develop resistance, which leads to a poor outcome. Chemotherapy works in a defined manner and this study explores the role of a molecule called insulin-like growth factor binding protein-2 (IGFBP-2), frequently increased by tumours, in the response of cancer cells to chemotherapy. This work suggests that reducing IGFBP-2 has the potential to improve sensitivity to chemotherapy and may provide insight into optimising current treatment strategies. The role if insulin-like growth factor binding protein-2 (IGFBP-2) in mediating chemoresistance in breast cancer cells has been demonstrated, but the mechanism of action is unclear. This study aimed to further investigate the role of IGFBP-2 in the DNA damage response induced by etoposide in MCF-7, T47D (ER+ve), and MDA-MB-231 (ER-ve) breast cancer cell lines. In the presence or absence of etoposide, IGFBP-2 was silenced using siRNA in the ER-positive cell lines, or exogenous IGFBP-2 was added to the ER-negative MDA-MB-231 cells. Cell number and death were assessed using trypan blue dye exclusion assay, changes in abundance of proteins were monitored using Western blotting of whole cell lysates, and localization and abundance were determined using immunofluorescence and cell fractionation. Results from ER-positive cell lines demonstrated that upon exposure to etoposide, loss of IGFBP-2 enhanced cell death, and this was associated with a reduction in P-DNA-PKcs and an increase in γH2AX. Conversely, with ER-negative cells, the addition of IGFBP-2 in the presence of etoposide resulted in cell survival, an increase in P-DNA-PKcs, and a reduction in γH2AX. In summary, IGFBP-2 is a survival factor for breast cancer cells that is associated with enhancement of the DNA repair mechanism. [ABSTRACT FROM AUTHOR]