Expression of cancer-associated fibroblast related proteins in metastatic breast cancer: an immunohistochemical analysis

Background: Cancer-associated fibroblast (CAF) is the most studied element of the tumor microenvironment, although no relationship has been identified between expression of their related proteins and the metastasis site. The purpose of this study was to investigate the expression of CAF related proteins and their implications according to the metastasis site in metastatic breast cancer. Methods: Immunohistochemical staining was used to evaluate the expression of CAF related proteins (podoplanin, prolyl 4-hydroxylase, FAP alpha, S100A4, PDGFR alpha, PDGFR beta, and NG2) in tissue microarrays from 132 cases of metastatic breast cancer (bone metastasis: 32 cases, brain metastasis: 38 cases, liver metastasis: 10 cases, and lung metastasis: 52 cases). Breast cancer subtypes were classified as luminal A, luminal B, HER-2, and triple negative breast cancer, according to the immunohistochemical staining results for estrogen and progesterone receptors, HER-2, and Ki-67 and FISH results for HER-2. Tumors were classified as desmoplastic, sclerotic, normal-like, and inflammatory type, according to the histologic findings from the tumor stroma. Results: Various CAF related protein expression profiles were observed, according to the metastasis site. For bone metastasis, the expression of stromal podoplanin, S100A4, and PDGFR alpha was significantly high. For lung metastasis, the expression of stromal PDGFR beta was significantly elevated (p < 0.001). For liver metastasis, significantly reduced expression of stromal S100A4 (p = 0.002) and PDGFR alpha (p = 0.011) was observed. Expression of CAF related proteins also differed according to the stromal phenotype. Desmoplastic stroma exhibited significantly elevated expression of stromal podoplanin (p < 0.001), S100A4 (p < 0.001), PDGFR alpha (p = 0.010), and PDGFR beta (p = 0.021). Inflammatory stroma exhibited significantly elevated expression of stromal FAP alpha (p = 0.044) and significantly reduced stromal S100A4 expression (p < 0.001). Sclerotic stroma exhibited significantly elevated tumoral FAP alpha (p = 0.005) expression. For lung metastasis, shorter overall survival was significantly related to tumoral podoplanin expression (p = 0.006), stromal podoplanin expression (p = 0.018), tumoral prolyl 4-hydroxylase negativity (p = 0.016), and tumoral PDGFR alpha expression (p = 0.001). Conclusion: For metastatic breast cancer, significant differences were observed in the expression of CAF related proteins, according to the metastasis site and stromal histologic phenotype.