Abstract: Objective: To observe the tumorigenesis of spontaneous breast cancer in F1 hybrids of TA Ⅰ and TAⅡ mice and to investigate the underlying mechanism. Methods: The hybrids of female TA Ⅱ and male TA Ⅰ werenamed F1 and the hybrids of female TA Ⅰ and male TA Ⅱ were named F1'. The F1 and F1' hybrids were observed fortumorigenesis. PCNA, Ki-67, P53 and Rb were detected by immunohistochemistry. Results: Eight of the 9 F1 femaleswere found with spontaneous breast cancer and it was 201 days on average before the cancer was observed. The averageparity was 7.67. Three of the 8 F1' females were found with spontaneous breast cancer and it was 190 days on average be-fore the cancer was observed. The average parity was 7.67. The spontaneous breast cancer was identified as adenocarcino-ma by pathology. Immunohistochemistry showed that PCNA and Rb were expressed in the spontaneous breast cancer tis-sues, while Ki-67 and P53 were not. The cells of spontaneous breast cancer were arrested in the G1 phase of the cell cy-cle. Conclusion: Maternal inheritance may play an important role in the tumorigenesis of spontaneous breast cancer in TAⅡ mice. The frequency of pregnancy may be positively correlated with tumorigenesis. Similar to pregnancy-associatedbreast cancer in human beings, there was a close relationship between pregnancy and spontaneous breast cancer in mice.High levels of estrogen and progesterone in the blood, the involution of the mammary glands, the changes in immune sta-tus during pregnancy and breastfeeding may play a part in tumorigenesis. This research provides a favourable model tostudy pregnancy-associated breast cancer.