δEF1 promotes osteolytic metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression.
Breast cancer metastasis is supposed to involve several stages in which epithelial-mesenchymal transition (EMT) is regarded as the mechanistic basis for the behavior of cancer cells. Our recent studies have implicated that δEF1, a member of the zinc finger-homeodomain transcription factor family, is required for governing both breast cancer EMT and bone remodeling, highlighting a potential role of δEF1 in modulating bone metastasis of breast cancer. In the present study, we further demonstrated that conditioned medium derived from δEF1-overexpressing MDA-MB-231 cells significantly induces osteoclast maturation and concurrently represses osteoblast differentiation and mineralization. On the contrary, conditioned medium derived from δEF1-interfered MDA-MB-231 cells exhibits an opposite effect, thus confirming the effect of δEF to mediate osteolytic metastasis of breast cancer. Furthermore, we found that, during this process, δEF1 remarkably up-regulates matrix metalloproteinase-1 (MMP-1) expression at both mRNA and protein levels in MDA-MB-231 cells. Importantly, the results of luciferase and CHIP assays indicated that δEF1 activates MMP-1 promoter activity through the AP-1 response element. Overexpression of δEF1 in MDA-MB-231 cells significantly increases the recruitment of the AP-1 components, c-Jun/c-Fos, to the endogenous MMP-1 promoter, which in effect could be mediated via the MAPK signaling pathway. In conclusion, these observations suggest a potent role of δEF1 to promote breast cancer metastasis to bone by regulating secretion of growth factors in the tumor microenvironment.
Medical College of Nankai University, 94 Weijin Road, Tianjin, China. ihufen@126.com
Fen
F
Hu
Chuan
C
Wang
Shaocong
S
Guo
Wei
W
Sun
Dong
D
Mi
Yang
Y
Gao
Jie
J
Zhang
Tianhui
T
Zhu
Shuang
S
Yang
D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1