Research article

Gene expression profiling of the tumor microenvironment during breast cancer progression

Xiao-Jun Ma¹ , Sonika Dahiya² , Elizabeth Richardson² , Mark Erlander¹ and Dennis C Sgroi²

¹  bioTheranostics, Inc., 11025 Roselle Street, Suite 200, San Diego, CA 92121, USA

²  Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA

author email corresponding author email

Breast Cancer Research 2009, 11:R7doi:10.1186/bcr2222

Published:	2 February 2009

See related editorial by Schedin and Borges, http://breast-cancer-research.com/content/11/2/102

Abstract

Introduction

The importance of the tumor microenvironment in breast cancer has been increasingly recognized. Critical molecular changes in the tumor stroma accompanying cancer progression, however, remain largely unknown. We conducted a comparative analysis of global gene expression changes in the stromal and epithelial compartments during breast cancer progression from normal to preinvasive to invasive ductal carcinoma.

Methods

We combined laser capture microdissection and gene expression microarrays to analyze 14 patient-matched normal epithelium, normal stroma, tumor epithelium and tumor-associated stroma specimens. Differential gene expression and gene ontology analyses were performed.

Results

Tumor-associated stroma undergoes extensive gene expression changes during cancer progression, to a similar extent as that seen in the malignant epithelium. Highly upregulated genes in the tumor-associated stroma include constituents of the extracellular matrix and matrix metalloproteases, and cell-cycle-related genes. Decreased expression of cytoplasmic ribosomal proteins and increased expression of mitochondrial ribosomal proteins were observed in both the tumor epithelium and the stroma. The transition from preinvasive to invasive growth was accompanied by increased expression of several matrix metalloproteases (MMP2, MMP11 and MMP14). Furthermore, as observed in malignant epithelium, a gene expression signature of histological tumor grade also exists in the stroma, with high-grade tumors associated with increased expression of genes involved in immune response.

Conclusions

Our results suggest that the tumor microenvironment participates in tumorigenesis even before tumor cells invade into stroma, and that it may play important roles in the transition from preinvasive to invasive growth. The immune cells in the tumor stroma may be exploited by the malignant epithelial cells in high-grade tumors for aggressive invasive growth.