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Chemotherapeutic resistance in breast cancer, whether acquired or intrinsic, remains a major clinical obstacle. Thus, increasing tumor cell sensitivity to chemotherapeutic agents will be helpful in improving the clinical management of breast cancer. In the present study, we found an induction of  HO ‐1 expression in doxorubicin ( DOX )‐treated  MDA ‐ MB ‐231 human breast adenocarcinoma cells, which showed insensitivity to  DOX  treatment. Knockdown  HO ‐1 expression dramatically upregulated the incidence of  MDA ‐ MB ‐231 cell death under  DOX  treatment, indicating that  HO ‐1 functions as a critical contributor to drug resistance in  MDA ‐ MB ‐231 cells. We further observed that  DOX  exposure induced a cytoprotective autophagic flux in  MDA ‐ MB ‐231 cells, which was dependent on  HO ‐1 induction. Moreover, upregulation of  HO ‐1 expression required the activation of both signal transducer and activator of transcription ( STAT )3 and its upstream regulator, protein kinase Src. Abrogating Src/ STAT 3 pathway activation attenuated  HO ‐1 and autophagy induction, thus increasing the chemosensitivity of  MDA ‐ MB ‐231 cells. Therefore, we conclude that Src/ STAT 3‐dependent  HO ‐1 induction protects  MDA ‐ MB ‐231 breast cancer cells from  DOX ‐induced death through promoting autophagy. In the following study, we further demonstrated the contribution of Src/ STAT 3/ HO ‐1/autophagy pathway activation to  DOX  resistance in another breast cancer cell line,  MDA ‐ MB ‐468, which bears a similar phenotype to  MDA ‐ MB ‐231 cells. Therefore, activation of Src/ STAT 3/ HO ‐1/autophagy signaling pathway might play a general role in protecting certain subtypes of breast cancer cells from  DOX ‐induced cytotoxicity. Targeting this signaling event may provide a potential approach for overcoming  DOX  resistance in breast cancer therapeutics.

Src/ STAT 3‐dependent heme oxygenase‐1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy