Tumour but not stromal expression of β3 integrin is essential, and is required early, for spontaneous dissemination of bone-metastatic breast cancer.

Carter,RZ, Micocci,KC, Natoli,A, Redvers,RP, Paquet-Fifield,S, Martin,AC, Denoyer,D, Ling,X, Kim,SH, Tomasin,R, Selistre-de-Araújo,H, Anderson,RL and Pouliot,N 2015, Tumour but not stromal expression of β3 integrin is essential, and is required early, for spontaneous dissemination of bone-metastatic breast cancer., Journal of Pathology, vol. 235, no. 5, pp. 760-772, doi: 10.1002/path.4490.

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Title Tumour but not stromal expression of β3 integrin is essential, and is required early, for spontaneous dissemination of bone-metastatic breast cancer.
Author(s) Carter,RZ
Micocci,KC
Natoli,A
Redvers,RP
Paquet-Fifield,S
Martin,AC
Denoyer,DORCID iD for Denoyer,D orcid.org/0000-0001-8932-5116
Ling,X
Kim,SH
Tomasin,R
Selistre-de-Araújo,H
Anderson,RL
Pouliot,N
Journal name Journal of Pathology
Volume number 235
Issue number 5
Start page 760
End page 772
Publisher Wiley
Place of publication England
Publication date 2015-04
ISSN 1096-9896
Keyword(s) DisBa-01
bone metastasis
breast cancer
syngeneic mouse model
vitronectin
β3 integrin
Summary Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in cancer progression, β3 inhibitors have shown only modest efficacy in patients with advanced solid tumours. The limited efficacy of β3 inhibitors in patients could arise from our incomplete understanding of the precise function of β3 integrin and, consequently, inappropriate clinical application. Data from animal studies are conflicting and indicate heterogeneity with respect to the relative contributions of β3-expressing tumour and stromal cell populations in different cancers. Here we aimed to clarify the function and relative contributions to metastasis of tumour versus stromal β3 integrin in clinically relevant models of spontaneous breast cancer metastasis, with particular emphasis on bone metastasis. We show that stable down-regulation of tumour β3 integrin dramatically impairs spontaneous (but not experimental) metastasis to bone and lung without affecting primary tumour growth in the mammary gland. Unexpectedly, and in contrast to subcutaneous tumours, orthotopic tumour vascularity, growth and spontaneous metastasis were not altered in mice null for β3 integrin. Tumour β3 integrin promoted migration, protease expression and trans-endothelial migration in vitro and increased vascular dissemination in vivo, but was not necessary for bone colonization in experimental metastasis assays. We conclude that tumour, rather than stromal, β3 expression is essential and is required early for efficient spontaneous breast cancer metastasis to bone and soft tissues. Accordingly, differential gene expression analysis in cohorts of breast cancer patients showed a strong association between high β3 expression, early metastasis and shorter disease-free survival in patients with oestrogen receptor-negative tumours. We propose that β3 inhibitors may be more efficacious if used in a neoadjuvant setting, rather than after metastases are established. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Language eng
DOI 10.1002/path.4490
Field of Research 111201 Cancer Cell Biology
111207 Molecular Targets
111209 Solid Tumours
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, Wiley
Persistent URL http://hdl.handle.net/10536/DRO/DU:30071481

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