Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors

Kristina A. Trujillo, Christopher M Heaphy, Minh Mai, Keith M. Vargas, Anna C. Jones, Phung Vo, Kimberly S. Butler, Nancy E. Joste, Marco Bisoffi, Jeffrey K. Griffith

Research output: Contribution to journalArticle

Abstract

Previous studies have shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The extent, composition and biological significance of this field are only partially understood, but the molecular alterations in affected cells could provide mechanisms for limitless replicative capacity, genomic instability and a microenvironment that supports tumor initiation and progression. We demonstrate by microarray, qRT-PCR and immunohistochemistry a signature of differential gene expression that discriminates between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm and 5 cm from the margins of breast adenocarcinomas (TAHN-1 and TAHN-5, respectively). The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis and epithelial to mesenchymal transition (EMT). Myofibroblasts, which are mediators of wound healing and fibrosis, and intra-lobular fibroblasts expressing MMP2, SPARC, TGF-β3, which are inducers of EMT, were both prevalent in TAHN-1 tissues, sparse in TAHN-5 tissues, and absent in normal tissues from reduction mammoplasty. Accordingly, EMT markers S100A4 and vimentin were elevated in both luminal and myoepithelial cells, and EMT markers α-smooth muscle actin and SNAIL were elevated in luminal epithelial cells of TAHN-1 tissues. These results identify cellular processes that are differentially activated between TAHN-1 and TAHN-5 breast tissues, implicate myofibroblasts as likely mediators of these processes, provide evidence that EMT 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.

Original languageEnglish (US)
Pages (from-to)1310-1321
Number of pages12
JournalInternational Journal of Cancer
Volume129
Issue number6
DOIs
StatePublished - Sep 15 2011

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Epithelial-Mesenchymal Transition
Fibrosis
Breast Neoplasms
Breast
Myofibroblasts
Wound Healing
Tumor Microenvironment
Mammaplasty
Genomic Instability
Vimentin
Transcriptome
Extracellular Matrix
Smooth Muscle
Actins
Adenocarcinoma
Fibroblasts
Biomarkers
Epithelial Cells
Immunohistochemistry
Polymerase Chain Reaction

Keywords

  • breast cancer
  • epithelial to mesenchymal transition
  • fibrosis
  • field cancerization
  • wound healing

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. / Trujillo, Kristina A.; Heaphy, Christopher M; Mai, Minh; Vargas, Keith M.; Jones, Anna C.; Vo, Phung; Butler, Kimberly S.; Joste, Nancy E.; Bisoffi, Marco; Griffith, Jeffrey K.

In: International Journal of Cancer, Vol. 129, No. 6, 15.09.2011, p. 1310-1321.

Research output: Contribution to journalArticle

Trujillo, Kristina A. ; Heaphy, Christopher M ; Mai, Minh ; Vargas, Keith M. ; Jones, Anna C. ; Vo, Phung ; Butler, Kimberly S. ; Joste, Nancy E. ; Bisoffi, Marco ; Griffith, Jeffrey K. / Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. In: International Journal of Cancer. 2011 ; Vol. 129, No. 6. pp. 1310-1321.
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AU - Jones, Anna C.

AU - Vo, Phung

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AU - Griffith, Jeffrey K.

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