Microenvironmental Changes in DCIS: Myoepithelial Cells Change from Tumour Suppressor to Tumour Promoter.
2009
Background: The mechanism of transition of ductal carcinoma in-situ (DCIS) to invasive cancer is poorly understood but recently changes in the microenvironment have been implicated. A unique feature of the DCIS microenvironment is the presence of a myoepithelial population. Normal myoepithelial cells (MECs) have a broad tumour suppressor function but these cells show changes in gene expression and phenotype in DCIS.Hypothesis: We hypothesised that during the evolution of DCIS breast myoepithelial cells undergo a switch in gene expression profile that compromises their suppressor function and may lead to promotion of tumour progression.Materials and methods: To investigate this, Immuno-Laser Capture Microdissection was used to isolate MECs from normal and DCIS breast tissues followed by whole genome expression profiling using Affymetrix HGU-133 plus2.0 arrays. The data were analysed using Bioconductor (www.bioconductor.org) packages within the open source R statistical environment (www.r-project.org). We set a double threshold for significant changes in gene expression with a False Discovery Rate (FDR) 50%) and presence of invasion (p=0.006). Moreover, culture of normal and DCIS-modified MEC lines on a Fibronectin matrix revealed that FN1 modifies MEC function and abrogates their tumour suppressor activity.Other key alterations identified and validated include up-regulation of the recently characterised Nephronectin and down-regulation of PTHLH, FGFR2, ADAMTS5, TGFBR3, and CAV2, each of which has been implicated in suppressing tumour growth and invasion or inhibition of angiogenesis.Conclusion and significance: This is the first study to use this in-vivo technique to investigate molecular changes in MEC in DCIS and to reveal that DCIS associated MECs show up-regulation of the tumour-promoting molecule FN1. Our data support the hypothesis that there is switch in MEC function from suppressor to potential promoter activity that can influence the progression of in-situ to invasive disease and may lead to novel predictive and therapeutic targets. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4161.
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