GGNBP2 suppresses triple-negative breast cancer aggressiveness through inhibition of IL-6/STAT3 signaling activation
- 114 Downloads
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, lacking effective targeted therapies, and whose underlying mechanisms are still unclear. The gene coding for Gametogenetin-binding protein (GGNBP2), also known as Zinc Finger Protein 403 (ZNF403), is located on chromosome 17q12-q23, a region known as a breast cancer susceptibility locus. We have previously reported that GGNBP2 functions as a tumor suppressor in estrogen receptor-positive breast cancer. The aim of this study was to evaluate the role and mechanisms of GGNBP2 in TNBC.
The effect of GGNBP2 on TNBC aggressiveness was investigated both in vitro and in vivo. The protein and mRNA expression levels were analyzed by western blotting and reverse transcription quantitative polymerase chain reaction, respectively. Fluorescence-activated cell sorting analysis was used to evaluate the cell cycle distribution and cell apoptosis. Immunohistochemistry was used to determine the expression of GGNBP2 in breast cancer tissues.
We find that GGNBP2 expression decreases in TNBC tissues and is associated with the outcome of breast cancer patients. Furthermore, experimental overexpression of GGNBP2 in MDA-MB-231 and Cal51 cells suppresses cell proliferation, migration and invasion, reduces the cancer stem cell subpopulation, and promotes cell apoptosis in vitro as well as inhibits tumor growth in vivo. In these cell models, overexpression of GGNBP2 decreases the activation of IL-6/STAT3 signaling.
Our data demonstrate that GGNBP2 suppresses cancer aggressiveness by inhibition of IL-6/STAT3 activation in TNBC.
KeywordsTriple-negative breast cancer STAT3 GGNBP2
This study was supported by the Tianjin Natural Sciences Foundation (17JCQNJC09900 to YH) and the National Natural Science Foundation of China (No. 81672623 to ZJ). EY thanks Breast Cancer Now for supporting research in his laboratory.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 3.Ohbayashi T, Oikawa K, Iwata R, Kameta A, Evine K, Isobe T, Matsuda Y, Mimura J, Fujii-Kuriyama Y, Kuroda M, Mukai K (2001) Dioxin induces a novel nuclear factor, DIF-3, that is implicated in spermatogenesis. FEBS Lett 508(3):341–344Google Scholar
- 9.Li S, Moore AK, Zhu J, Li X, Zhou H, Lin J, He Y, Xing F, Pan Y, Bohler HC, Ding J, Cooney AJ, Lan Z, Lei Z (2016) Ggnbp2 is essential for pregnancy success via regulation of mouse trophoblast stem cell proliferation and differentiation. Biol Reprod 94(2):41. https://doi.org/10.1095/biolreprod.115.136358 Google Scholar
- 15.Lan ZJ, Hu Y, Zhang S, Li X, Zhou H, Ding J, Klinge CM, Radde BN, Cooney AJ, Zhang J, Lei Z (2016) GGNBP2 acts as a tumor suppressor by inhibiting estrogen receptor alpha activity in breast cancer cells. Breast Cancer Res Treat 158(2):263–276. https://doi.org/10.1007/s10549-016-3880-2 Google Scholar
- 22.Zhou Z, Li M, Zhang L, Zhao H, Sahin O, Chen J, Zhao JJ, Songyang Z, Yu D (2018) Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts nononcogenic PKM2 to a tumor promoter and induces cancer stem-like cells. Cancer Res 78(9):2248–2261. https://doi.org/10.1158/0008-5472.CAN-17-2726 Google Scholar
- 24.Asaduzzaman M, Constantinou S, Min H, Gallon J, Lin ML, Singh P, Raguz S, Ali S, Shousha S, Coombes RC, Lam EW, Hu Y, Yague E (2017) Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer. Breast Cancer Res Treat 163(3):461–474. https://doi.org/10.1007/s10549-017-4202-z Google Scholar
- 26.Balko JM, Schwarz LJ, Bhola NE, Kurupi R, Owens P, Miller TW, Gomez H, Cook RS, Arteaga CL (2013) Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res 73(20):6346–6358. https://doi.org/10.1158/0008-5472.CAN-13-1385 Google Scholar
- 28.Yanai A, Inoue N, Yagi T, Nishimukai A, Miyagawa Y, Murase K, Imamura M, Enomoto Y, Takatsuka Y, Watanabe T, Hirota S, Sasa M, Katagiri T, Miyoshi Y (2015) Activation of mTOR/S6K but not MAPK pathways might be associated with high Ki-67, ER(+), and HER2(–) breast cancer. Clin Breast Cancer 15(3):197–203. https://doi.org/10.1016/j.clbc.2014.12.002 Google Scholar
- 29.Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R, Wu Z, Gonen M, Mulvey LA, Bessarabova MO, Huh SJ, Silver SJ, Kim SY, Park SY, Lee HE, Anderson KS, Richardson AL, Nikolskaya T, Nikolsky Y, Liu XS, Root DE, Hahn WC, Frank DA, Polyak K (2011) The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(–) stem cell-like breast cancer cells in human tumors. J Clin Invest 121(7):2723–2735. https://doi.org/10.1172/JCI44745 Google Scholar
- 30.Couture LA, Harris MW, Birnbaum LS (1990) Characterization of the peak period of sensitivity for the induction of hydronephrosis in C57BL/6N mice following exposure to 2,3,7, 8-tetrachlorodibenzo-p-dioxin. Fundam Appl Toxicol 15(1):142–150Google Scholar
- 31.Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA (2003) Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport. Exp Cell Res 289(2):211–221Google Scholar
- 34.Zhou Y, Hu Y, Yang M, Jat P, Li K, Lombardo Y, Xiong D, Coombes RC, Raguz S, Yague E (2014) The miR-106b ~ 25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300. Cell Death Differ 21(3):462–474. https://doi.org/10.1038/cdd.2013.167 Google Scholar
- 36.Attar N, Kurdistani SK (2017) Exploitation of EP300 and CREBBP lysine acetyltransferases by cancer. Cold Spring Harb Perspect Med 7 (3). https://doi.org/10.1101/cshperspect.a026534