1: Clin Cancer Res. 2004 Oct 15;10(20):6789-95. 

Molecular profiling of inflammatory breast cancer: identification of a
poor-prognosis gene expression signature.

Bieche I, Lerebours F, Tozlu S, Espie M, Marty M, Lidereau R.

Laboratoire d'Oncogenetique - INSERM E0017, Centre Rene Huguenin, St-Cloud,
France. i.bieche@stcloud-huguenin.org

PURPOSE: Inflammatory breast cancer (IBC) is a rare but particularly aggressive
form of primary breast cancer. The molecular mechanisms responsible for IBC are
largely unknown. EXPERIMENTAL DESIGN: To obtain further insight into the
molecular pathogenesis of IBC, we used real-time quantitative reverse
transcription (RT)-PCR to quantify the mRNA expression of 538 selected genes in
IBC relative to non-IBC. RESULTS: Twenty-seven (5.0%) of the 538 genes were
significantly up-regulated in IBC compared with non-IBC. None were
down-regulated. The 27 up-regulated genes mainly encoded transcription factors
(JUN, EGR1, JUNB, FOS, FOSB, MYCN, and SNAIL1), growth factors (VEGF,
DTR/HB-EGF, IGFBP7, IL6, ANGPT2, EREG, CCL3/MIP1A, and CCL5/RANTES) and growth
factor receptors (TBXA2R, TNFRSF10A/TRAILR1, and ROBO2). We also identified a
gene expression profile, based on MYCN, EREG, and SHH, which discriminated
subgroups of IBC patients with good, intermediate, and poor outcome. CONCLUSION:
Our study has identified a limited number of signaling pathways that require
inappropriate activation for IBC development. Some of the up-regulated genes
identified here could offer useful diagnostic or prognostic markers and could
form the basis of novel therapeutic strategies.

PMID: 15501955 [PubMed - indexed for MEDLINE]


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2: Cancer Res. 2000 Feb 1;60(3):712-21. 

Integrins alpha(v)beta3 and alpha(v)beta5 are expressed by endothelium of
high-risk neuroblastoma and their inhibition is associated with increased
endogenous ceramide.

Erdreich-Epstein A, Shimada H, Groshen S, Liu M, Metelitsa LS, Kim KS, Stins MF,
Seeger RC, Durden DL.

Division of Hematology-Oncology, Children's Hospital Los Angeles, University of
Southern California School of Medicine, 90027, USA.

Inhibition of the RGD-binding integrins, alpha(v)beta3 and alpha(v)beta5,
prevents endothelial cell anchorage and induces endothelial apoptosis, which
results in disruption of tumor angiogenesis and inhibition of tumor growth in
animal models. In this study, we demonstrate by immunohistochemical analysis
that integrin alpha(v)beta3 was expressed by 61% (mean) of microvessels in
high-risk neuroblastomas (stage IV and MYCN-amplified stage III; n = 28) but
only by 18% (mean) of microvessels in low-risk tumors (stages I and II and
non-MYCN-amplified stage III; n = 12). Integrin alpha(v)beta5 was found on 60%
(mean) of microvessels in 21 Stage IV tumors. These data suggest that
neuroblastomas may be targeted for antiangiogenic treatment directed against
endothelial integrins alpha(v)beta3 and alpha(v)beta5. In cell culture,
inhibition of integrin-dependent endothelial cell anchorage to vitronectin by
RGDfV, an RGD function-blocking cyclic peptide, induced apoptosis in bovine
brain endothelial cells compared with the control peptide, RADfV (37.5% versus
8.7%, respectively), as detected by chromatin condensation and nuclear
fragmentation. Treatment with RGDfV but not with RADfV, which prevented
attachment of endothelial cells to vitronectin or fibronectin, was associated
with up to a 50% increase in endogenous ceramide, a lipid second messenger that
can mediate cell death. Furthermore, exogenous C2-ceramide was cytotoxic to
bovine brain endothelial cells and induced activation of C-jun N-terminal kinase
(JNK), a MAP kinase that can be activated in stress-induced apoptosis pathways.
This suggests that ceramide may function in detachment-induced endothelial cell
apoptosis, originating from inhibition of vitronectin binding to integrins such
as alpha(v)beta3 and alpha(v)beta5. This is the first report to demonstrate
expression of integrins alpha(v)beta3 and alpha(v)beta5 by microvascular
endothelium of a childhood tumor and association of their expression with
neuroblastoma aggressiveness. Furthermore, our data provide the first suggestion
that inhibition of endothelial cell anchorage, resulting from specific blockade
of RGD-binding integrins, increases endogenous ceramide, which may contribute to
endothelial cell death.

PMID: 10676658 [PubMed - indexed for MEDLINE]


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