Generation and characterization of a breast carcinoma model by PyMT overexpression in mammary epithelial cells of tree shrew, an animal close to primates in evolution

Guang-Zhe Ge  ^{1   2} , Hou-Jun Xia  ¹ , Bao-Li He  ³ , Hai-Lin Zhang  ¹ , Wen-Jing Liu  ^{1   2} , Ming Shao  ^{1   2} , Chun-Yan Wang  ^{1   4} , Ji Xiao  ^{1   2} , Fei Ge  ^{1   5} , Fu-Bing Li  ¹ , Yi Li  ⁶ , Ceshi Chen  ¹

• ¹ Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
• ² Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China.
• ³ Department of Laboratory Animal Science, Kunming Medical University, Kunming, Yunnan, 650500, China.
• ⁴ Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China.
• ⁵ Department of Endocrine Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
• ⁶ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Abstract

The tree shrew is becoming an attractive experimental animal model for human breast cancer owing to a closer relationship to primates/humans than rodents. Tree shrews are superior to classical primates because tree shrew are easier to manipulate, maintain and propagate. It is required to establish a high-efficiency tree shrew breast cancer model for etiological research and drug assessment. Our previous studies suggest that 7,12-dimethylbenz(a)anthracene (DMBA) and medroxyprogesterone acetate (MPA) induce breast tumors in tree shrews with a low frequency (<50%) and long latency (∼ 7-month), making these methods less than ideal. We induced mammary tumors in tree shrew (Tupaia belangeri chinensis) by injection of lentivirus expressing the PyMT oncogene into mammary ducts of 22 animals. Most tree shrews developed mammary tumors with a latency of about three weeks, and by 7 weeks all injected tree shrews had developed mammary tumors. Among these, papillary carcinoma is the predominant tumor type. One case showed lymph node and lung metastasis. Interestingly, the expression levels of phosphorylated AKT, ERK and STAT3 were elevated in 41-68% of PyMT-induced mammary tumors, but not all tumors. Finally, we observed that the growth of PyMT-induced tree shrew mammary tumors was significantly inhibited by Cisplatin and Epidoxorubicin. PyMT-induced tree shrew mammary tumor model may be suitable for further breast cancer research and drug development, due to its high efficiency and short latency.

Keywords: PyMT; animal model; breast cancer; tree shrew.