FOXC1 expression is associated with a triple-negative basal-like phenotype in breast cancer

Introduction: Triple-negative breast carcinoma (TNBC) is a group of aggressive tumors that are resistant to hormonal therapy. Forkhead box C1 (FOXC1) has been shown to play a crucial role in cancer pathogenesis by cancer stem cell regulation, epithelial to mesenchymal transition and tumor progression in basal-like breast cancer (BLBC). This study examined the expression of FOXC1 in basal-like TNBC, which may potential be exploited as a treatment target for this group of tumors. 
Materials and Methods: Immunohistochemical Peroxidase-DAB system and Opal immunofluorescence staining system were employed to detect FOXC1 and cytokeratin 14 (CK14) expressions in 44 formalin-fixed paraffin-embedded (FFPE) invasive ductal breast carcinoma (IDC) and 150 IDC samples on tissue microarray. CK14 was used to identify the BLBC subtype. The staining was scored semi-quantitatively according to the intensity with a mean score from 0-4. 
Results: CK14 identified 15 (34%) BLBC in the FFPE tissues and 24 (16%) BLBC in the samples on tissue microarray. Of the 44 FFPE tissues, FOXC1 expression was observed in 100% of the BLBC and 83% of TNBC, while it was only found in 15% of non-TNBC. The mean staining intensity of FOXC1 was lower in non-TNBC (0.30) compared to TNBC (2.16) and basal-like TNBC (2.60). These findings were confirmed in the tissue microarray, which also revealed a strong positive correlation of FOXC1 with basal-like TNBC. In addition, our results showed that FOXC1 was more frequently expressed in ER-negative (22%), PR-negative (21%) and HER2-negative (19%) breast cancers than in ER-positive (3%), PR-positive (3%) and HER2-positive (5%) breast cancers. Moreover, FOXC1 expression was significantly associated with high tumor grade (p = 0.000041) and high tumor-infiltrating lymphocytes (TILs) (p = 0.000001). 
Conclusion: FOXC1 is highly expressed in TNBC, particularly among the basal-like subgroup, as opposed to other breast cancers. It accurately classifies the BLBC subtype which may be used as a surrogate marker for this molecular subtype. We find that FOXC1 has an inverse correlation with ER, PR and HER2, as well as a positive correlation with tumor grade and TILs. Our finding suggests that FOXC1 may serve as a potential treatment target for basal-like TNBC.