HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition.
Epithelial-mesenchymal transition (EMT) is increasingly recognized as a mechanism whereby cells in primary noninvasive tumors acquire properties essential for migration and invasion. Microarray analyses of microdissected epithelial cells from bone metastasis revealed a HOXB7 overexpression that was 3-fold higher than in primary breast carcinomas and 18-fold higher compared with normal breast. This led us to investigate the role of HOXB7 in neoplastic transformation of breast cells. Expression of HOXB7 in both MCF10A and Madin-Darby canine kidney (MDCK) epithelial cells resulted in the acquisition of both phenotypic and molecular attributes typical of EMT. Loss of epithelial proteins, claudin 1 and claudin 7, mislocalization of claudin 4 and E-cadherin, and the expression of mesenchymal proteins, vimentin and alpha-smooth muscle actin, were observed. MDCK cells expressing HOXB7 exhibited properties of migration and invasion. Unlike MDCK vector-transfected cells, MDCK-HOXB7 cells formed highly vascularized tumors in mice. MDCK-HOXB7 cells overexpressed basic fibroblast growth factor (bFGF), had more active forms of both Ras and RhoA proteins, and displayed higher levels of phosphorylation of p44 and p42 mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinases 1 and 2). Effects initiated by HOXB7 were reversed by specific inhibitors of FGF receptor and the Ras-MAPK pathways. These data provide support for a function for HOXB7 in promoting tumor invasion through activation of Ras/Rho pathway by up-regulating bFGF, a known transcriptional target of HOXB7. Reversal of these effects by HOXB7-specific siRNA further suggested that these effects were mediated by HOXB7. Thus, HOXB7 overexpression caused EMT in epithelial cells, accompanied by acquisition of aggressive properties of tumorigenicity, migration, and invasion.
Wu
Xinyan
X
Breast Cancer Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Chen
Hexin
H
Parker
Belinda
B
Rubin
Ethel
E
Zhu
Tao
T
Lee
Ji Shin
JS
Argani
Pedram
P
Sukumar
Saraswati
S
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D018631:ras Proteins / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000502:physiology
C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein