Westbury, C. B., Reis-Filho, J. S., Dexter, T., Mahler-Araujo, B., Fenwick, K., Iravani, M., Grigoriadis, A., Parry, S., Robertson, D., Mackay, A., Ashworth, A., Yarnold, J. R., Isacke, C. M. (2009) Genome-wide transcriptomic profiling of microdissected human breast tissue reveals differential expression of KIT (c-Kit, CD117) and oestrogen receptor-alpha (ER alpha) in response to therapeutic radiation. JOURNAL OF PATHOLOGY, 219 (1). pp. 131-140. ISSN 0022-3417

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Abstract

The pathogenesis of late normal tissue fibrosis after high-dose ionizing radiation involves multiple cell types and signalling pathways but is not well understood. To identify the molecular changes occurring after radiotherapy, paired normal tissue samples were collected from the non-irradiated breast and from the treated breast of women who had undergone curative radiotherapy for early breast cancer months or years previously. As radiation may induce distinct transcriptional changes in the different components of the breast, laser capture microdissection and gene expression microarray profiling were performed separately for epithelial and stromal components and selected genes were validated using immunohistochemistry. In the epithelial compartment, a reduction of KIT (c-Kit; CD117) and a reciprocal increase in ESR1 (oestrogen receptor-alpha, ER alpha) mRNA and protein levels were seen in irradiated compared to non-irradiated samples. In the stromal compartment, extracellular matrix genes including FN1 (fibronectin 1) and CTGF (connective tissue growth factor; CCN2) were increased. Further investigation revealed that c-Kit and ERa were expressed in distinct subpopulations of luminal epithelial cells. Interlobular c-Kit-positive mast cells were also increased in irradiated cases not showing features of post-radiation atrophy. Pathway analysis revealed `cancer, reproductive system disease and tumour morphology' as the most significantly enriched network in the epithelial compartment, whereas in the stromal component, a significant enrichment for `connective tissue disorders, dermatological diseases and conditions, genetic disorder' and `cancer, tumour morphology, infection mechanism' networks was observed. These data identify previously unreported changes in the epithelial compartment and show altered expression of genes implicated in late normal tissue injury in the stromal compartment of normal breast tissue. The findings are relevant to both fibrosis and atrophy occurring after radiotherapy for early breast cancer. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Item Type:	Article
Authors (ICR Faculty only):	Isacke, Clare and Yarnold, John and Ashworth, Alan and Reis-Filho, Jorge
All Authors:	Westbury, C. B., Reis-Filho, J. S., Dexter, T., Mahler-Araujo, B., Fenwick, K., Iravani, M., Grigoriadis, A., Parry, S., Robertson, D., Mackay, A., Ashworth, A., Yarnold, J. R., Isacke, C. M.
Uncontrolled Keywords:	breast; radiation fibrosis; c-Kit; oestrogen receptor; mast cell; stem cell factor; laser capture microdissection; gene expression microarray; pathway analysis;MAST-CELLS; MICROARRAY ANALYSIS; ENTERITIS; COLLAGEN
Funding Acknowledgement:	Breakthrough Breast Cancer ; Institute of Cancer Research ; Cancer Research UK Section of Radiotherapy (CRUK) [C46/A2131]; NHS
Funding Text:	We thank Sunil Lakhani and Catherine Clarke for discussions in the early stage of this project and Ashutosh Nerurkar and Ann Pearson for help with tissue collection. This work was supported by Breakthrough Breast Cancer, the Institute of Cancer Research, and the Cancer Research UK Section of Radiotherapy (CRUK), grant number C46/A2131. We acknowledge NHS funding to the NIHR Biomedical Research Centre.
Research teams:	Closed research groups > Molecular Pathology ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function ICR divisions > Breast Cancer Research > Molecular Cell Biology ICR divisions > Radiotherapy and Imaging > Clinical Academic Radiotherapy (Yarnold)
Depositing User:	Users 10 not found.
Date Deposited:	21 Sep 2009 12:11
Last Modified:	18 Feb 2014 16:42
URI:	http://publications.icr.ac.uk/id/eprint/8723

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