Enhancement of mammary tumour growth by IGFBP-3 involves impaired T cell accumulation

    1. Robert C Baxter1
    1. 1Hormones and Cancer Laboratories, Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia
    2. 2School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, Australia
    3. 3Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Jersey, USA
    4. 4Charles Perkins Centre, Sydney Medical School, University of Sydney, New South Wales, Australia
    1. Correspondence should be addressed to R C Baxter: robert.baxter{at}sydney.edu.au


    Epidemiological studies show an association between obesity and poor breast cancer prognosis. We previously demonstrated that global IGFBP-3 deficiency, in IGFBP-3-null mice, resulted in a 50% reduction in mammary tumour growth over 3 weeks relative to tumours in wild-type (WT) C57BL/6 mice. This growth reduction was ameliorated by high fat feeding-induced obesity. This study aimed to examine how IGFBP-3 promotes tumour growth by influencing the immune tumour microenvironment in healthy and obese mice. Syngeneic EO771 cells, which lack detectable IGFBP-3 expression, were grown as orthotopic tumours in WT and IGFBP-3-null C57BL/6 mice placed on either a control chow or a high-fat diet (HFD), and examined by quantitative PCR and immunohistochemistry. In WT mice, increased stromal expression of IGFBP-3 was positively associated with tumour growth, supporting the hypothesis that IGFBP-3 in the microenvironment promotes tumour progression. Examining markers of immune cell subsets, gene expression of Ifng, Cd8a, Cd8b1 and Tnf and CD8 measured by immunohistochemistry were elevated in tumours of IGFBP-3-null mice compared to WT, indicating an accumulation of CD8+ T cells, but this increase was absent if the IGFBP-3-null mice had been exposed to HFD. Expression of these genes was negatively associated with tumour growth. Although similar among groups overall, Nkg2d and Tnfsf10 tumoural expression was associated with decreased tumour growth. Overall, the results of this study provide an immune-based mechanism by which host IGFBP-3 may promote breast tumour growth in the EO771 murine breast cancer model, and suggest that targeting IGFBP-3 might make a novel contribution to immune therapy for breast cancer.

    • Received 19 October 2017
    • Accepted 31 October 2017
    • Made available online as an Accepted Preprint 7 December 2017
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