HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition.

Abstract

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.

• Authors: Xinyan Wu, Hexin Chen, Belinda Parker, Ethel Rubin, Tao Zhu, Ji Shin Lee, Pedram Argani, Saraswati Sukumar
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 19 Pg. 9527-34 (Oct 01 2006) ISSN: 1538-7445 [Electronic] United States
• PMID: 17018609 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• HOXB7 protein, human
• Homeodomain Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• Recombinant Fusion Proteins
• Fibroblast Growth Factor 2
• ras Proteins
• rhoA GTP-Binding Protein

Topics

• Animals
• Bone Neoplasms (metabolism, secondary)
• Breast Neoplasms (metabolism, pathology)
• Carcinoma, Ductal, Breast (metabolism, pathology, secondary)
• Cell Transformation, Neoplastic (genetics)
• Dogs
• Epithelial Cells (cytology, metabolism, pathology)
• Female
• Fibroblast Growth Factor 2 (biosynthesis, genetics)
• Gene Expression Profiling
• Homeodomain Proteins (biosynthesis, genetics, physiology)
• Humans
• MAP Kinase Signaling System
• Mesoderm (pathology)
• Mice
• Mice, Nude
• Neoplasm Invasiveness (genetics)
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• RNA, Small Interfering (pharmacology)
• Recombinant Fusion Proteins (physiology)
• Transfection
• ras Proteins (physiology)
• rhoA GTP-Binding Protein (physiology)