Characteristics of Field Cancerization in Histologically Normal Tissue Adjacent to Breast Tumors

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It has been shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The characteristics of this field are not fully understood, although it is clear that the molecular alterations in affected cells could provide mechanisms for increased replicative capacity, genomic instability, and a microenvironment that supports tumor initiation and progression.

Trujillo and colleagues from the University of New Mexico, Albuquerque, and Johns Hopkins School of Medicine, Baltimore, recently identified a gene signature that differentiated between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm from the margin of breast adenocarcinomas and those located 5 cm from the margin. The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis, and epithelial to mesenchymal transition (EMT).

Role of Myofibroblasts

Myofibroblasts, which are mediators of wound healing and fibrosis, and intralobular fibroblasts expressing MMP2, SPARC, TGF-β3, which are inducers of epithelial to mesenchymal transition, were both prevalent in tumor-adjacent histologically normal tissues 1 cm from the margin, sparse in tumor-adjacent histologically normal tissues 5 cm from the margin, and absent in normal tissues (from reduction mammoplasty). In tumor-adjacent histologically normal tissues 1 cm from the margin, the epithelial-mesenchymal transition markers S100A4 and vimentin were elevated in luminal epithelial and myoepithelial cells and the epithelial-mesenchymal transition markers α-smooth muscle actin and SNAIL were elevated in luminal epithelial cells.

As stated by the investigators, “These results identify cellular processes that are differentially activated between [tumor-adjacent histologically normal breast tissues 1 cm from the margin and those tissues 5 cm from the margin], implicate myofibroblasts as likely mediators of these processes, provide evidence that [epithelial to mesenchymal transition] is occurring in histologically normal tissues within the affected field, and identify candidate biomarkers to investigate whether or how field cancerization contributes to the development of primary or recurrent breast tumors.”■

Trujillo KA, et al: Int J Cancer 129:1310-1321, 2011.