Objective Compare the depression phenotypes of a breast cancer tumor-bearing mouse model constructed using two different method and a mouse model of breast cancer depression with clinical manifestations, as well as assess their suitability for basic research. Methods We constructed a tumor model with 4T1 breast cancer cells alone (4T1 group)and a tumor-depression composite model given chronic unpredictable mild (CUMS) (4T1 +CUMS group). The experimental period was 42 d, and the body mass, tumor volume, and survival time of the mice were monitored throughout the whole process. Two depressive behavioral tests (of sucrose preference test, open field test, tail suspension test, and elevated plus maze ) were performed on the 15th and 29th days, respectively. Hematoxylin-eosin (HE)staining was used to observe the pathological changes of hippocampal neurons in brain tissue sections. Results (1)Body mass: The body mass of the 4T1 group and 4T1 + CUMS group began to decrease from29 d, and the body mass of the 4T1 + CUMS group was significantly lower than that of the 4T1 group and Control group at the end of the experiment (P<0. 001). (2) Tumor volume: There was no significant difference in the growth rate of tumors between the two model groups throughout the experiment (P>0. 05). (3)Survival time: The survival rates of the 4T1 group and 4T1 + CUMS group were 100% and 60%, and the first death of mice in the 4T1 + CUMS group was on the 36th day. (4) Behavior test of depression: There was no significant difference between the three groups in the first depressive behavior tests (P>0. 05), and the two groups showed obvious depressive phenotypes in the second behavioral tests. The sucrose preference index and activity distance in the central area were significantly decreased in the two model groups (P<0. 001), and the immobility time was significantly increased (P<0. 001).(5)Pathological section of brain tissue: On pathological examination of brain tissue, we observed a reduced number of neuronal cells in the hippocampus of the 4T1 group and 4T1 + CUMS group, their morphology was irregular, the arrangement between the cells was disordered and the gap was unclear, and some nucleoli were blurred. Conclusions Although the tumor-only method and the tumor with compound stress stimulation method can both be used to prepare breast cancer depression models, the tumor-only modeling method is simpler and the mortality rate after successful modeling is higher. The long window of time is convenient for subsequent drug administration and detection, and the causes of the depression phenotype are more in line with the clinical causes and manifestations. Therefore, the 4T1 model can provide a reference model for future animal experiments on breast cancer tumor-related depression.