Dataset Information

E-GEOD-20086

ABSTRACT: Heterogeneity of gene expression in stromal fibroblasts of human breast carcinomas and normal breast

OTHER RELATED OMICS DATASETS IN: PRJNA124285

PROVIDER: E-GEOD-20086 | ExpressionAtlas | 2025-01-24

REPOSITORIES: ExpressionAtlas

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			Action	DRS
	E-GEOD-20086-analysis-methods.tsv	Tabular
	E-GEOD-20086-atlasExperimentSummary.Rdata	Rdata
	E-GEOD-20086-configuration.xml	Xml
	E-GEOD-20086-percentile-ranks.tsv	Tabular
	E-GEOD-20086.condensed-sdrf.tsv	Tabular

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Project description:Background: The terminal duct lobular unit (TDLU) is the most dynamic structure in the human breast and the putative site of origin of human breast cancer. Although stromal cells contribute to a specialized microenvironment in many organs, this component remains largely understudied in the human breast. We here demonstrate the impact on epithelium of two lineages of breast stromal fibroblasts, one of which accumulates in the TDLU while the other resides outside the TDLU in the interlobular stroma. Methods: The two lineages are prospectively isolated by FACS based on different expression levels of CD105 and CD26. The characteristics of the two fibroblast lineages are assessed by immunocytochemical staining and gene expression analysis. The differentiation capacity of the two fibroblast populations is determined by exposure to specific differentiating conditions followed by analysis of adipogenic and osteogenic differentiation. To test whether the two fibroblast lineages are functionally imprinted by their site of origin, single cell sorted CD271low/MUC1high normal breast luminal epithelial cells are plated on fibroblast feeders for the observation of morphological development. Epithelial structure formation and polarization is shown by immunofluorescence and digitalized quantification of immunoperoxidase stained cultures. Results: Lobular fibroblasts are CD105high/CD26low while interlobular fibroblasts are CD105low/CD26high. Once isolated the two lineages remain phenotypically stable and functionally distinct in culture. Lobular fibroblasts have properties in common with bone marrow derived mesenchymal stem cells and they specifically convey growth and branching morphogenesis of epithelial progenitors. Conclusions: Two distinct functionally specialized fibroblast lineages exist in the normal human breast, of which the lobular fibroblasts have properties in common with mesenchymal stem cells and support epithelial growth and morphogenesis. We propose that lobular fibroblasts constitute a specialized microenvironment for human breast luminal epithelial progenitors, i.e. the putative precursors of breast cancer.

Project description:Personalized biological insights into heterogeneous tumors, such as breast cancer could improve clinical management. While genomic analysis has contributed significantly towards dissecting breast cancer heterogeneity, limitations in clinical application are partly rooted in the inter-tumor variability arising from a largely uncharacterized interactive exchange between diverse cell types in the tumor microenvironment. Here we first identified a common response signature to stromal coculture across breast cancer of varying clinicopathologic phenotypes. Proximity to fibroblasts resulted in gene transcript alterations of >2-fold for 107 probe sets, collectively designated as Fibroblast Triggered Gene Expression in Tumor (FTExT). Prominent features of tumor cell response included transcript repression related to biofunctions encompassing inflammatory signaling, cell movement, cell death, and cell growth and proliferation. In an evaluation of intertumor heterogeneity, the FTExT classifier stratified moderate and high histopathologic grade breast cancer according to clinical outcome (dataset 1, n=401, p=0.031; dataset 2, n=200, p=0.013), delineating a novel phenotype of stromal crosstalk underlying the prognostic potential of tumor grade. Extending correlative data through functional analysis of stromal-epithelial cocultures of both malignant and nonmalignant derivation, significant differences in cell cycle regulation, rate of proliferation, resistance to therapy-induced apoptosis, and growth arrest were observed in FTExT-based subgroups. Instead of a stromal impact that is uniformly cancer promoting, our data demonstrate striking variability in tumor cell response that directly contributes to contrasting functional aggressiveness of malignant breast tissue. Our findings uniquely reveal dynamically interacting paracrine components underlying the molecular and functional heterogeneity of breast cancer, thus presenting novel opportunities for tumor targeting. 10 tumor samples cocultured with fibroblast were profiled in their gene expression with microarrays, and compared with 7 tumor samples cultured without fibroblast. Immortalized tumor cell lines of varying histologic grade were developed and maintained in a growth median as described in Dairkee, et al., Oncogene, 2007. In the coculture set up, epithelial cells were seeded in 6-well plates, and fibroblasts in 0.4 μm inserts with hanging geometry (BD Biosciences, Franklin Lakes, NJ) at a 3:1 ratio in a common pool of growth medium for 3-day harvests. Controls were comprised of each epithelial sample maintained in the absence of fibroblast-seeded inserts under the same culture conditions.