Du Jiaxing, Zhao Qi, Liu Kai, Li Zugui, Fu Fangmei, Zhang Kexin, Zhang Hao, Zheng Minying, Zhao Yongjie, Zhang Shiwu
Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Department of Pathology, Tianjin Union Medical Center, Tianjin, China.
Front Oncol. 2020 May 5;10:652. doi: 10.3389/fonc.2020.00652. eCollection 2020.
The Tientsin Albino 2 (TA2) mouse has a high incidence of spontaneous breast cancer (SBC) in the absence of external inducers or carcinogens. The initiation of SBC is related to mouse mammary tumor virus (MMTV) infection and pregnancy. Pathologic analysis showed that breast cancer cells in TA2 mice are triple negative. Our previous study confirmed that fibroblast growth factor receptor 2 (FGFR2) expression increased in SBC tissue compared to that in their corresponding normal breast tissues of TA2 mice. The present study focused on the function of the FGFR2/STAT3 signaling pathway in the initiation of SBC. In this study, the expression of FGF3, FGFR2, STAT3, p-STAT3, and p-STAT3 was detected in serum and normal mammary gland tissues of TA2 mice with different number of pregnancies and SBC. The proliferation, invasiveness, and migration abilities of MA-891 cells from TA2 SBC were compared before and after cryptotanshinone and Stattic treatment. Transient siRNA transfection was used to detect the invasiveness, and migration abilities to avoid the off-targets effects. Downstream protein expression of STAT3 was also detected in MA-891 cells and TA2 xenografts from MA-891 inoculation. In addition, STAT3 expression was analyzed in 139 cases of human breast cancer including 117 cases of non-triple negative breast cancer (non-TNBC) (group I) and 22 cases of triple-negative breast cancer (TNBC) (group II). Results of our study confirmed that MMTV-LTR amplification, and FGFR2, p-STAT3, p-STAT3 expression increased with the number of pregnancies in the breast tissue of TA2 mice and were the highest in SBC. Serum FGF3 expression of SBC was higher than it of TA2 mice with different number of pregnancies. After STAT3 was inhibited, the abilities of proliferation, invasiveness, and migration in MA-891 decreased and the expression levels of STAT3, p-STAT3, p-STAT3, Bcl2, cyclin D1, and c-myc in MA-891 and animal xenografts were also down-regulated. In human breast cancer, STAT3 expression was significantly higher in TNBC than that in non-TNBC. Our results showed that the FGFR2/STAT3 signaling pathway may be related to SBC initiation in TA2 mice. Inhibition of STAT3 can decrease proliferation, invasiveness, and migration in MA-891 cells and the growth of TA2 xenografts.
天津白化病2号（TA2）小鼠在没有外部诱导剂或致癌物的情况下，自发性乳腺癌（SBC）的发病率很高。SBC的起始与小鼠乳腺肿瘤病毒（MMTV）感染和妊娠有关。病理分析表明，TA2小鼠的乳腺癌细胞为三阴性。我们之前的研究证实，与TA2小鼠相应的正常乳腺组织相比，SBC组织中成纤维细胞生长因子受体2（FGFR2）的表达增加。本研究聚焦于FGFR2/STAT3信号通路在SBC起始中的作用。在本研究中，检测了不同妊娠次数的TA2小鼠以及SBC小鼠血清和正常乳腺组织中FGF3、FGFR2、STAT3、p-STAT3和p-STAT3的表达。比较了隐丹参酮和Stattic处理前后TA2 SBC的MA-891细胞的增殖、侵袭和迁移能力。使用瞬时siRNA转染来检测侵袭和迁移能力，以避免脱靶效应。还检测了MA-891细胞以及接种MA-891的TA2异种移植瘤中STAT3的下游蛋白表达。此外，分析了139例人类乳腺癌中STAT3的表达，其中包括117例非三阴性乳腺癌（非TNBC）（第一组）和22例三阴性乳腺癌（TNBC）（第二组）。我们的研究结果证实，MMTV-LTR扩增以及FGFR2、p-STAT3、p-STAT3的表达在TA2小鼠乳腺组织中随妊娠次数增加而升高，且在SBC中最高。SBC的血清FGF3表达高于不同妊娠次数的TA2小鼠。抑制STAT3后，MA-891细胞的增殖、侵袭和迁移能力下降，MA-891细胞和动物异种移植瘤中STAT3、p-STAT3、p-STAT3、Bcl2、细胞周期蛋白D1和c-myc的表达水平也下调。在人类乳腺癌中，TNBC中STAT3的表达明显高于非TNBC。我们的结果表明，FGFR2/STAT3信号通路可能与TA2小鼠的SBC起始有关。抑制STAT3可降低MA-891细胞的增殖、侵袭和迁移能力以及TA2异种移植瘤的生长。
