Interactions between breast cancer cells and their stromal component: an analysis of alterations in gene expression
C.
Sotiriou, F. El Ouriaghli, S. Majjaj, B. Haibe-Kains, C. Desmedt, F. Lallemand, D. Larsimont, M. Piccart
Background:
Epithelial-stromal interactions are known to be important in normal
mammary gland development and to play a role in breast carcinogenesis.
The aim of this study was to explore the influence of breast tumor
microenvironment on primary tumor growth, breast cancer sub-typing and
prognosis.
Methods: Myo-fibroblast cells
(CD10) were isolated and purified from breast tumor (N= 28) and normal
(N=4) tissues. Gene expression analysis was performed using the
Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Survival
analysis was carried out using 12 publicly available microarray
datasets including more than 1200 systemically untreated breast cancer
patients.
Results: Breast tumor
myo-fibroblast stroma cells showed an altered gene expression patterns
to the ones isolated from normal breast tissues. While some of the
differentially expressed genes are found to be associated with
extracellular matrix formation/degradation and angiogenesis, the
function of several other genes remains largely unknown. Unsupervised
hierarchical clustering analysis clustered breast tumor myo-fibroblast
cells into subgroups recapitulating the molecular portraits of breast
cancer based on ER, HER2 status and tumor differentiation. A stroma
gene expression signature developed from myo-fibroblast cells isolated
from normal versus BC tissues showed a statistically significant
association with clinical outcome. Breast tumors with high expression
levels of the stroma signature were significantly associated with worse
prognosis (HR 1.55; CI 1.20-1.99; p=5.57 10-4). This association was
only observed within the clinically high risk HER2+ subtypes.
Interestingly, HER2+ tumors with high and low expression levels of the
stroma signature showed 45% and 85% distant metastasis free survival at
5-year follow-up respectively (HR 2.53; CI 1.31-4.90; p=5.29 10-3).
Conclusions: Our results
highlight the importance of tumor epithelial-stroma cell interactions
in breast carcinogenesis and breast cancer sub-typing. Moreover, it
shows the role of stroma cells in tumor dissemination particularly
within the HER2+ subtype and provide basis for the development of novel
therapeutic strategies.