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

Xinyan Wu, Hexin Chen, Belinda Parker, Ethel Rubin, Tao Zhu, Ji Shin Lee, Pedram Argani, Saraswati Sukumar

Research output: Contribution to journalArticle

139 Citations (Scopus)

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 α-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.

Original languageEnglish (US)
Pages (from-to)9527-9534
Number of pages8
JournalCancer Research
Volume66
Issue number19
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

Fingerprint

Homeodomain Proteins
Madin Darby Canine Kidney Cells
Epithelial-Mesenchymal Transition
Breast Neoplasms
Epithelial Cells
Fibroblast Growth Factor 2
Breast
Claudin-4
rhoA GTP-Binding Protein
MAP Kinase Kinase 2
Neoplastic Cell Transformation
Claudin-1
ras Proteins
Fibroblast Growth Factor Receptors
Neoplasms
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Vimentin
Cadherins
Microarray Analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. / Wu, Xinyan; Chen, Hexin; Parker, Belinda; Rubin, Ethel; Zhu, Tao; Lee, Ji Shin; Argani, Pedram; Sukumar, Saraswati.

In: Cancer Research, Vol. 66, No. 19, 01.10.2006, p. 9527-9534.

Research output: Contribution to journalArticle

Wu, X, Chen, H, Parker, B, Rubin, E, Zhu, T, Lee, JS, Argani, P & Sukumar, S 2006, 'HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition', Cancer Research, vol. 66, no. 19, pp. 9527-9534. https://doi.org/10.1158/0008-5472.CAN-05-4470
Wu, Xinyan ; Chen, Hexin ; Parker, Belinda ; Rubin, Ethel ; Zhu, Tao ; Lee, Ji Shin ; Argani, Pedram ; Sukumar, Saraswati. / HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. In: Cancer Research. 2006 ; Vol. 66, No. 19. pp. 9527-9534.
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