Genomic instability in the breast microenvironment? A critical evaluation of the evidence

Tumor-associated stroma plays an active role in breast pathogenesis, with alterations in cell signaling, proliferation and angiogenesis contributing to successful tumorigenesis. Although epigenetic modifications to DNA, as well as changes in RNA and protein expression have been identified in tumor-associated stroma, there is considerable debate regarding the presence of chromosomal alterations, detected as loss of heterozygosity/allelic imbalance events in histologically normal stromal cells adjacent to the breast carcinomas. Previous studies have detected loss of heterozygosity/allelic imbalance at varying distances from the tumor margin, and patterns of chromosomal change have been linked to tumor grade and lymph node status. By contrast, recent reports challenge the presence of genomic instability in stromal cells of the breast tumor microenvironment, leading to the speculation that the loss of heterozygosity/allelic imbalance studies, based almost exclusively on microsatellite-based profiling of formalin-fixed, paraffin-embedded tissues, do not accurately measure the true genomic content of the tumor microenvironment but rather are a reflection of technological artifact. In this perspective, we present evidence surrounding the debate and critically evaluate arguments, both pros and cons, over the presence or absence of genomic instability tumor-associated stroma.