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Published online before print April 10, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070988

Accepted for publication January 23, 2008.

Article

Molecular Characterization of Human Breast Tumor Vascular Cells

Rajendra Bhati*, Cam Patterson{dagger}, Chad A. Livasy{ddagger}{sect}, Cheng Fan{ddagger}, David Ketelsen{ddagger}, Zhiyuan Hu{ddagger}, Evangeline Reynolds{ddagger}, Catherine Tanner*, Dominic T. Moore{ddagger}, Franco Gabrielli, Charles M. Perou{ddagger}{sect}||, and Nancy Klauber-DeMore*{dagger}{ddagger}@

From the Department of Surgery,* Carolina Cardiovascular Biology Center,{dagger} Lineberger Comprehensive Cancer Center,{ddagger} Department of Pathology and Laboratory Medicine,{sect} and Department of Genetics,|| University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Experimental Pathology and Medical Biotechnology, University of Pisa, Pisa, Italy

@ To whom correspondence should be addressed. E-mail: nancy_demore{at}med.unc.edu.


  Abstract

A detailed understanding of the assortment of genes that are expressed in breast tumor vessels is needed to facilitate the development of novel, molecularly targeted anti-angiogenic agents for breast cancer therapies. Rapid immunohistochemistry using factor VIII-related antibodies was performed on sections of frozen human luminal-A breast tumors (n = 5) and normal breast (n = 5), followed by laser capture microdissection of vascular cells. RNA was extracted and amplified, and fluorescently labeled cDNA was synthesized and hybridized to 44,000-element long-oligonucleotide DNA microarrays. Statistical analysis of microarray was used to compare differences in gene expression between tumor and normal vascular cells, and Expression Analysis Systematic Explorer was used to determine enrichment of gene ontology categories. Protein expression of select genes was confirmed using immunohistochemistry. Of the 1176 genes that were differentially expressed between tumor and normal vascular cells, 55 had a greater than fourfold increase in expression level. The extracellular matrix gene ontology category was increased while the ribosome gene ontology category was decreased. Fibroblast activation protein, secreted frizzled-related protein 2, Janus kinase 3, and neutral sphingomyelinase 2 proteins localized to breast tumor endothelium as assessed by immunohistochemistry, showing significantly greater staining compared with normal tissue. These tumor endothelial marker proteins also exhibited increased expression in breast tumor vessels compared with that in normal tissues. Therefore, these genetic markers may serve as potential targets for the development of angiogenesis inhibitors.






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Copyright © 2008 by the American Society for Investigative Pathology.