Characterization and clinical evaluation of CD10+ stroma cells in the breast cancer microenvironment

Abstract

Purpose: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10(+) stromal cells, we aimed to better characterize this cell population and its clinical relevance.

Experimental design: We developed a CD10(+) stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10(+) cells by coculture experiments of representative breast cancer cell lines with the different CD10(+) stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets.

Results: This 12-gene CD10(+) stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10(+) cell types contribute to the CD10(+) stroma signature, although mesenchymal stem cells have the highest CD10(+) stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2(+) subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients.

Conclusions: Our results highlight the importance of CD10(+) cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2(+) breast cancer disease.

Figure 1

Heat map representing the expression of the genes included in the CD10⁺ stroma signature in the normal and tumor-associated CD10⁺ cells (red represents high expression values and green low expression values). The molecular subtypes of the tumor samples are illustrated for each tumor sample. ER and HER2 were both assessed by immunohistochemistry. ER⁺/HER2⁻ (low) were ER⁺/HER2⁻ tumors of grade 1 or 2 and ER⁺/HER2⁻ (high) were ER⁺/HER2⁻ tumors of grade 3.

Figure 2

Box plots representing the CD10⁺ stroma signature and the CD10⁺ signature genes in the different CD10⁺ cell types (cocultures with different subtypes of breast cancer cell lines and controls are represented separately).

Figure 3

Box plots representing the CD10⁺ stroma signature score and the individual gene expression values between the IDC and DCIS groups from Schuetz and colleagues (14) originally profiled on the Affymetrix HG U133Plus2.0. *P < 0.01; **P < 0.001.

Figure 4

Survival curves for untreated patients stratified by the CD10⁺ stroma signature: all patients (A), ER⁻ /HER2 ⁻ (B), HER2⁺ (C), and ER⁺/HER2 ⁻ (D).

Figure 5

Receiver operator characteristic curve analysis of the ability of the CD10⁺ stroma signature and the A-score to discriminate patients with pathologic complete response from patients with residual disease in the TOP trial: all ER⁻ patients (A), ER⁻/HER2⁻ (B), and ER⁻/HER2⁺ (C). AUC, area under the curve.