Clinical and functional significance of α9β1 integrin expression in breast cancer: a novel cell-surface marker of the basal phenotype that promotes tumour cell invasion

Abstract

Integrin α9β1 is a receptor for ECM proteins, including Tenascin-C and the EDA domain of fibronectin, and has been shown to transduce TGFβ signalling. This study has examined the expression pattern of α9β1 in 141 frozen breast carcinoma samples and related expression to prognostic indices, molecular subtype and patient outcome. Effects of α9β1 on tumour cell migration and invasion were assessed using blocking antibody and gene transduction approaches. Integrin α9β1 localized to myoepithelial cells in normal ducts and acini, a pattern maintained in DCIS. A subset (17%) of invasive carcinomas exhibited tumour cell expression of α9β1, which related significantly to the basal-like phenotype, as defined by either CK5/6 or CK14 expression. Tumour expression of α9β1 showed a significant association with reduced overall patient survival (p < 0.0001; HR 5.94, 95%CI 3.26-10.82) and with reduced distant-metastasis-free survival (p < 0.0001; HR 6.37, CI 3.51-11.58). A series of breast cancer cell lines was screened for α9β1 with the highly invasive basal-like GI-101 cell line expressing significant levels. Both migration and invasion of this line were reduced significantly in the presence of α9-blocking antibody and following α9-knockdown with siRNA. Conversely, migratory and invasive behaviour of α9-negative MCF7 cells and α9-low MDA MB468 cells was enhanced significantly by over-expression of α9. Thus, α9β1 acts as a novel marker of the basal-like breast cancer subtype and expression is associated with reduced survival, while its ability to promote breast cancer cell migration and invasion suggests that it contributes to the aggressive clinical behaviour of this tumour subtype.