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Thrombospondin-4 expression is activated during the stromal response to invasive breast cancer

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Abstract

The thromobospondins are a family of extracellular glycoproteins that are activated during tissue remodeling processes such as embryogenesis, wound healing and cancer. Thrombospondin-4 (THBS4) is known to have roles in cellular migration, adhesion and attachment, as well as proliferation in different contexts. Data to support a role in cancer biology is increasing, including for gastrointestinal and prostate tumours. Here, using a combination of immunohistochemistry, immunofluorescence and analysis of publicly available genomic and expression data, we present the first study describing the pattern of expression of THBS4 in normal breast and breast cancer. THBS4 was located to the basement membrane of large ducts and vessels in normal breast tissue, but was absent from epithelium and extracellular matrix. There was a significant induction in expression in cancer-associated stroma relative to normal stroma (P = 0.0033), neoplastic epithelium (P < 0.0001) and normal epithelium (P < 0.0001). There was no difference in stromal expression of THBS4 between invasive ductal carcinomas (IDC) and invasive lobular carcinomas (ILC). The THBS4 mRNA levels were variable yet were generally highest in tumours typically rich in stromal content (ILC, ER positive low grade IDC; luminal A and normal-like subtypes). Genomic alterations of the THBS4 gene (somatic mutations and gene copy number) are rare suggesting this dramatic activation in expression is most likely dynamically regulated through the interaction between invading tumour cells and stromal fibroblasts in the local microenvironment. In summary, THBS4 expression in breast cancer-associated extracellular matrix contributes to the activated stromal response exhibited during tumour progression and this may facilitate invasion of tumour cells.

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Acknowledgements

We thank the patients and their families for the tissues donated for research through the Brisbane Breast Bank and other tissue resources. PTS and ACV were recipients of fellowships from the National Breast Cancer Foundation, Australia and the Ludwig Institute of Cancer Research, respectively. This work was funded by a grant from the Cancer Council Queensland, Australia.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. The University of Queensland, UQ Centre for Clinical Research (UQCCR), Building 71/918, The Royal Brisbane & Women’s Hospital, Herston, Queensland, 4029, Australia

    Amy E. McCart Reed, Sarah Song, Jamie R. Kutasovic, Lynne E. Reid, Jordan M. Valle, Ana Cristina Vargas, Chanel E. Smart & Peter T. Simpson

  2. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Australia

    Sarah Song

  3. Pathology Queensland: The Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

    Ana Cristina Vargas

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  1. Amy E. McCart Reed
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Correspondence to Peter T. Simpson.

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Supplementary Table 1

Details of previous gene expression studies comparing ILC versus IDC (XLS 1239 kb)

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McCart Reed, A.E., Song, S., Kutasovic, J.R. et al. Thrombospondin-4 expression is activated during the stromal response to invasive breast cancer. Virchows Arch 463, 535–545 (2013). https://doi.org/10.1007/s00428-013-1468-3

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