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Understanding the response of cancer cells to anti-cancer therapies is crucial to unraveling and preventing the development of therapeutic resistance. The human AHNAK protein is a giant scaffold protein implicated in several diverse cellular functions. The role of AHNAK in cancer is however unclear as the protein has previously been described as a tumor suppressor, as well as being essential for tumor metastasis and invasion, while also being implicated in selected chemotherapeutic responses. To clarify the role of AHNAK in cancer, we investigated the effect of doxorubicin treatment on AHNAK in doxorubicin-sensitive MCF-7 and doxorubicin-resistant MDA-MB-231 breast cancer cell lines, as well as in a tumor-bearing mouse model. The role of AHNAK in the cellular response of breast cancer cells to doxorubicin was also investigated. We report here, for the first time, an association between AHNAK and resistance to doxorubicin. While treatment with doxorubicin modulated AHNAK protein expression both in vitro and in vivo in a dose-dependent manner, no changes in its cellular localization were observed. AHNAK knockdown prevented doxorubicin-induced modulation of cleaved caspase 7 protein expression and cell cycle arrest, while its overexpression decreased cleaved caspase 7 and cleaved PARP levels and induced S-phase arrest, changes that were comparable to the effects of doxorubicin. This novel association was restricted to doxorubicin-resistant cells, implicating the protein in therapeutic resistance. These findings confirm that AHNAK does indeed function in the chemotherapeutic response of breast cancer cells while also emphasizing the need for further investigation into potential implications for AHNAK in terms of predicting and modulating treatment response.