Alterations in vascular gene expression in invasive breast carcinoma.
The molecular signature that defines tumor microvasculature will likely provide clues as to how vascular-dependent tumor proliferation is regulated. Using purified endothelial cells, we generated a database of gene expression changes accompanying vascular proliferation in invasive breast cancer. In contrast to normal mammary vasculature, invasive breast cancer vasculature expresses extracellular matrix and surface proteins characteristic of proliferating and migrating endothelial cells. We define and validate the up-regulated expression of VE-cadherin and osteonectin in breast tumor vasculature. In contrast to other tumor types, invasive breast cancer vasculature induced a high expression level of specific transcription factors, including SNAIL1 and HEYL, that may drive gene expression changes necessary for breast tumor neovascularization. We demonstrate the expression of HEYL in tumor endothelial cells and additionally establish the ability of HEYL to both induce proliferation and attenuate programmed cell death of primary endothelial cells in vitro. We also establish that an additional intracellular protein and previously defined metastasis-associated gene, PRL3, appears to be expressed predominately in the vasculature of invasive breast cancers and is able to enhance the migration of endothelial cells in vitro. Together, our results provide unique insights into vascular regulation in breast tumors and suggest specific roles for genes in driving tumor angiogenesis.
Parker
Belinda S
BS
Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Argani
Pedram
P
Cook
Brian P
BP
Liangfeng
Han
H
Chartrand
Scott D
SD
Zhang
Mindy
M
Saha
Saurabh
S
Bardelli
Alberto
A
Jiang
Yide
Y
St Martin
Thia B
TB
Nacht
Mariana
M
Teicher
Beverly A
BA
Klinger
Katherine W
KW
Sukumar
Saraswati
S
Madden
Stephen L
SL
D001808:Blood Vessels / Q000378:metabolism*; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000098:blood supply / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000209:etiology*; D009479:Neuropeptides / Q000235:genetics; D015676:Osteonectin / Q000235:genetics
D058851:GPI-Linked Proteins; D009479:Neuropeptides; C105161:Nrn1 protein, rat; D015676:Osteonectin