Abstract
BackgroundThe Wilms’ tumour protein (WT1), which influences tumour development and angiogenesis, is a promising therapeutic target in breast cancer. We hypothesised that WT1 expression would vary in endothelial cells in distinct sub-classifications of breast cancer.MethodsWT1 expression and vascular density were quantified by immunohistochemical analysis of human (n = 57) and murine breast cancers. Human tumours were sub-classified by histopathological grade, ER status and HER2 enrichment.ResultsWT1 was identified in endothelial (and epithelial and smooth muscle) cells in tumours and tumour-free tissues (controls) from patients and mice with breast cancer. WT1 expression was higher in tumours than in controls, but this was not due to increased endothelial WT1. Vascular WT1 in cancers decreased as histopathological grade increased. WT1 was higher in ER-positive versus ER-negative cancers. Strikingly, reduced WT1 expression in controls correlated with an increased Nottingham Prognostic Index score.ConclusionsExpression of WT1 is increased in breast cancers but this is not limited to the vascular compartment. The association between reduced WT1 in tumour-free tissue and poor prognosis suggests a protective role for WT1 in the healthy breast.
Highlights
Breast cancer, the most common female malignancy across the developed. and developing world, is the primary cause of death among women globally.[1]
Since WT1 expression in the vascular endothelium is implicated in the regulation of angiogenesis,[17] increased expression of WT1 in endothelial cells may contribute to tumour formation, for example Wagner et al.[18] reported WT1 expression in endothelial cells in 95% of 113 solid tumours, yet WT1 was not expressed in adjacent healthy tissue
The percentage of vessels expressing Wt1 was greater in the tumours than control tissue of Friend Virus B-type (FVB) mice (Fig. 6j). This investigation addressed the hypothesis that WT1 expression is increased in vascular endothelial cells in human breast cancers
Summary
The most common female malignancy across the developed. and developing world, is the primary cause of death among women globally.[1]. WT1, a multi-functional gene fundamental to mammalian embryological development,[2,3,4] is normally only expressed in discrete sites in the adult (e.g. in the mesothelium surrounding the visceral organs, the glomerular podocytes of the kidney, the sertoli/granulosa cells of the testis/ovary and 1% of bone marrow cells).[5,6,7,8,9,10] substantial evidence, both from solid tumours and leukaemia, suggests a role for WT1 as an oncogene.[11,12,13,14,15] Such evidence linking WT1 expression with tumour formation led to the United States National Cancer Institute ranking WT1 as the cancer antigen with greatest potential as a target for immunotherapeutic agents.[16] since WT1 expression in the vascular endothelium is implicated in the regulation of angiogenesis,[17] increased expression of WT1 in endothelial cells may contribute to tumour formation, for example Wagner et al.[18] reported WT1 expression in endothelial cells in 95% of 113 solid (lung, ovarian, pancreatic, breast and bladder) tumours, yet WT1 was not expressed in adjacent healthy tissue. The association between reduced WT1 in tumour-free tissue and poor prognosis suggests a protective role for WT1 in the healthy breast
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