FGFR2/STAT3 Signaling Pathway Involves in the Development of MMTV-Related Spontaneous Breast Cancer in TA2 Mice

Abstract

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 Tyr705 , and p-STAT3 Ser727 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 Tyr705 , p-STAT3 Ser727 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 Ser727 , p-STAT3 Tyr705 , 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.

BCL2L15 Depletion Inhibits Endometrial Receptivity via the STAT1 Signaling Pathway

“…Previous studies showed that fludarabine treated HTR-8/SVneo cells only inhibited the STAT1 phosphorylation without changing the STAT1 protein status [41]. Du et al reported that the protein level of STAT3, p-STAT3 Ser727 , and p-STAT3 Tyr705 were inhibited by Stattic treatment in the MA-891 cells [42]. In deciphering the effects of the STAT1 and STAT3 pathways on endometrial receptivity during the peri-implantation period of pregnancy, we treated fludarabine and Stattic in shBCL2L15 EECs.…”

Clinicopathological Significances of Cancer Stem Cell-Associated HHEX Expression in Breast Cancer

“…In the present study, we found that HHEX expression was lower in BC and correlated with prognosis and clinicopathology in BC patients. Tientsin Albino 2 (TA2) mice have a high incidence of spontaneous BC (SBC) (Du et al, 2020 ). SBC initiation associates with the infection of mouse mammary tumor virus and pregnancy (Du et al, 2020 ).…”

Data_Sheet_3.doc

“…The difference of HHEX expression in breast tissue of TA2 mice with different pregnancies and SBC had statistical significance (F = 26.93, P < 0.001) (Figure 2Bb, Supplementary Figures 3, 4D). Breast tissue of TA2 mice with six pregnancies was proved to be precancerous lesion based on H&E staining (the result has been published in another paper (Du et al, 2020). Moreover, HHEX expression in SBC was downregulated ( Supplementary Table 3).…”

“…Tientsin Albino 2 (TA2) mice Abbreviations: HHEX, haematopoietically expressed homeobox/proline-rich homeodomain; TA2, Tientsin Albino 2 mouse; SBC, spontaneous breast cancer; BC, Breast Carcinoma; DEGs, Differentially expressed genes; RBP, RNA binding protein; OS, Overall Survival; RFS, Relapse-Free Survival; ER, Estrogen Receptor; PR, Progesterone Receptor; HER2, Epidermal Growth Factor Receptor 2; SBR, Scarff-Bloom & Richardson; NPI, Nottingham prognostic index; CSC, Cancer stem cell; IHC, Immunohistochemical staining. have a high incidence of spontaneous BC (SBC) (Du et al, 2020). SBC initiation associates with the infection of mouse mammary tumor virus and pregnancy (Du et al, 2020).…”