Introduction
Over several years, the majority of studies on breast carcinoma have focused only on the epithelial component; however, the tumor-associated stroma and particularly the cancer-associated fibroblasts (CAFs) have been found to play a crucial role in cancer pathogenesis (1,2).
We previously demonstrated that the majority of these CAFs were smooth muscle actin (SMA)-positive, with a myofibroblastic-like phenotype, and that the presence of these peritumoral myofibroblasts (PMYs) is crucial for in situ and invasive breast carcinoma of no special type (NST), as well in metastatic disease (3,4). The origin of PMYs remains debatable, but we previously demonstrated that the resident CD34-positive breast fibroblasts are able to acquire SMA myofibroblastic characteristics under the control of the transforming growth factor β-1 pathway (3). It was suggested that these PMYs promote tumor invasion, growth and angiogenesis through paracrine factors and/or direct cell-cell crosstalk (5). Therefore, it was suggested that CAFs/PMYs potentially secrete various proteins, particularly matrix metalloproteinase 2 (MMP2), to facilitate tumor invasion (6,7). To elucidate this issue, we immunohistochemically analyzed the expression of MMP2 in normal breast stromal fibroblasts and in CAFs/PMYs present in invasive breast carcinoma of NST, according to clinicopathological variables. Our data were reviewed according to the highlights of the recent literature.
Discussion
Several recent studies support the hypothesis that, in invasive breast carcinoma, the gene expression profile of the epithelial component and, therefore, the immunohistochemical profile surrogates of molecular classes, represent biologically distinct diseases with different response to therapy and clinical outcome (12,13). In addition to the epithelial cell autonomous processes, it has been hypothesized that the tumor microenvironment, and particularly CAFs, are able to promote tumor cell proliferation, angiogenesis and metastasis (3,4,14). Certain breast CAFs, which are characterized by SMA expression and are referred to as PMYs, appear to play an important role in metastasis, including lymph node metastasis (3,4). Therefore, similar to the epithelial counterpart, it was hypothesized that the tumor's aggressiveness may be affected by the stromal composition, as well as the stroma's own biological properties (‘stromal signature’) (15,16). In the present study, we demonstrated that the stromal expression of MMP2, which is known to promote cancer invasion and metastasis by degrading various components of the extracellular matrix, varies according to the different tumor subtypes. In particular, in HER2-positive (luminal-HER2 and HER2-enriched) and triple-negative tumors, stromal expression of MMP2 was more frequently detected compared with the luminal subtypes (Table II). Of note, it was recently indicated that, on multivariate analysis, luminal-HER2, HER2-enriched and triple-negative tumors are associated with a higher rate of distant metastasis, including brain, liver and lung metastases (13,17). Therefore, the metastatic potential may be determined by the intrinsic properties of the epithelial component of the different breast tumor subtypes, as well as by the stromal properties of the microenvironment, as in the present case, by expressing different MMP2 levels, which have been implicated in the degradation of extracellular matrix and the enhancement of tumor cell motility (18,19,7,20). In conclusion, different stromal properties, such as MMP2 expression, may predispose the different histological breast tumor subtypes to different metastatic outcomes. Further studies are in progress, with the aim to accurately characterize stromal properties based on breast cancer subtype classification.