Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models

// An-Qi Zeng 1, * , Yan Yu 1, * , Yu-Qin Yao 1, * , Fang-Fang Yang 1 , Mengya Liao 2 , Lin-Jiang Song 1 , Ya-Li Li 1 , Yang Yu 3 , Yu-Jue Li 1 , Yuan-Le Deng 1 , Shu-Ping Yang 1 , Chen-Juan Zeng 1, 4 , Ping Liu 5 , Yong-Mei Xie 1 , Jin-Liang Yang 1 , Yi-Wen Zhang 1 , Ting-Hong Ye 1 and Yu-Quan Wei 1 1 Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China 2 Sichuan Nursing Vocational College, Chengdu 610100, China 3 Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital Affiliated to the Capital Medical University, Beijing 100038, China 4 Sichuan Scientist Biotechnology Co., Ltd, Chengdu 610041, China 5 Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, China * These authors contributed equally to this work Correspondence to: Ting-Hong Ye, email: yeth1309@scu.edu.cn Yi-Wen Zhang, email: yiwenzhang@scu.edu.cn Keywords: betulinic acid; breast cancer; migration and invasion; pulmonary metastases; MDSCs Received: May 19, 2017      Accepted: November 27, 2017      Published: December 17, 2017 ABSTRACT Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo . BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.