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Breast cancer cells modulate lipid and fatty acid metabolism to sustain proliferation. The role of adipocytes in cancer treatment efficacy remains, however, to be fully elucidated. We investigated whether diet-induced obesity (DIO) affects the efficacy of doxorubicin treatment in a breast tumor-bearing mouse model. Female C57BL6 mice were fed a high fat or low fat diet for the full duration of the study (12 weeks). After 8 weeks, mice were inoculated with E0771 triple-negative breast cancer cells in the fourth mammary gland to develop breast tumor allographs. Tumor-bearing mice received either vehicle (Hank's balanced salt solution) or doxorubicin (chemotherapy). Plasma inflammatory markers, tumor, and mammary adipose tissue fatty acid composition, as well as protein expression of lipid metabolism markers were determined. The high fat diet (HFD) attenuated the treatment efficacy of doxorubicin. Both leptin and resistin concentrations were significantly increased in the HFD group treated with doxorubicin. Suppressed lipogenesis (decreased stearoyl CoA-desaturase-1) and lipolysis (decreased hormone-sensitive lipase) were observed in mammary adipose tissue of the DIO animals, whereas increased expression was observed in the tumor tissue of doxorubicin treated HFD mice. Obesogenic conditions induced altered tissue fatty acid (FA) compositions, which reduced doxorubicin's treatment efficacy. In mammary adipose tissue breast cancer cells suppressed the storage of FAs, thereby increasing the availability of free FAs and favored inflammation under obesogenic conditions.