title: Tumour but not stromal expression of β3 integrin is essential, and is required early, for spontaneous dissemination of bone-metastatic breast cancer.
abstract: 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.
authors.affiliation: Metastasis Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Rachel Zoe
authors.initials: RZ
authors.lastname: Carter
authors.forename: Kelli Cristina
authors.initials: KC
authors.lastname: Micocci
authors.forename: Anthony
authors.initials: A
authors.lastname: Natoli
authors.forename: Richard Paul
authors.initials: RP
authors.lastname: Redvers
authors.forename: Sophie
authors.initials: S
authors.lastname: Paquet-Fifield
authors.forename: Ana Carolina Baptista Moreno
authors.initials: AC
authors.lastname: Martin
authors.forename: Delphine
authors.initials: D
authors.lastname: Denoyer
authors.forename: Xiawei
authors.initials: X
authors.lastname: Ling
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Rebeka
authors.initials: R
authors.lastname: Tomasin
authors.forename: Heloisa
authors.initials: H
authors.lastname: Selistre-de-Araújo
authors.forename: Robin Lesley
authors.initials: RL
authors.lastname: Anderson
authors.forename: Normand
authors.initials: N
authors.lastname: Pouliot
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C061248:ITGB3 protein, human; D039661:Integrin beta3
keywords: DisBa-01; bone metastasis; breast cancer; syngeneic mouse model; vitronectin; β3 integrin