Increased Expression of LEF1 and β-Catenin in Invasive Micropapillary Carcinoma of the Breast is Associated With Lymphovascular Invasion and Lymph Node Metastasis

Abstract

Invasive micropapillary breast carcinoma (IMPC) is a rare breast cancer subtype characterized by small tumor cell clusters with loss of stromal attachment, an inside-out growth appearance, and lymphotropism. IMPC is associated with high incidence of lymphovascular invasion (LVI) and lymph node metastasis. Activated Wnt signaling has been implicated in the metastasis of other aggressive breast tumors, including triple-negative and basal-like carcinomas. In this study, we tested whether activated Wnt signaling could be detected in IMPC. Upon ligand binding, the central mediator of the Wnt pathway, β-catenin, accumulates in the cytosol and translocates to the nucleus where it forms a complex with lymphoid enhancer-binding factor 1 (LEF1) to regulate transcription. We performed immunostaining for β-catenin and LEF1 on a well-annotated cohort of 40 breast tumors and nodal metastases displaying micropapillary histopathology. Strong nuclear accumulation of β-catenin was not observed, however a dim cytosolic and/or nuclear accumulation of β-catenin was sometimes seen in IMPC and this expression pattern was significantly associated with nodal metastasis. β-catenin expression correlated with the upregulation of LEF1 in IMPC. LEF1 expression was detected in 26 of 40 (65%) cases and was specifically enriched at the invasive front of the tumor and in tumor clusters undergoing LVI. Detection of LEF1 expression in the primary tumor was associated with an increased rate of LVI, lymph node metastasis, and disease relapse. LEF1 and β-catenin expression levels were significantly higher in metastases compared with primary tumors. In summary, this study demonstrates an association between the upregulation of β-catenin/LEF1 and the metastasis of IMPC.

Advances in invasive micropapillary carcinoma of the breast research: A review

“…Involved in Rac1 expression and the reversal of cell polarity [26] LEF1 Wnt pathway activation [27] IL-1b Linked to increased microvessel density [28] SDF-1 Interacting with CXCR4 on lymphatic endothelial cells [29] molecule sLex is associated with the MUC1/EMA-mediated cellular polarity reversal that leads to enhanced LNM of IMPC. [24] The interaction between sLex, overexpressed on IMPC cell clusters, and E-selectin, highly expressed on lymph endothelial cell surfaces enables lymphatic invasion and LNM in IMPC.…”

“…However, shRNA transfection results show decreased plakoglobin concentration and the PI3K/Akt/BCL-2 pathway activity and suggest that plakoglobin may prevent apoptosis by activating the anti-metastatic pathway. Furthermore, Darin [ 27 ] immunohistochemically assessed the β-catenin and LEF1 expressions, prominent Wnt pathway activation markers in IMPC, and demonstrated a significant association between LEF1 expression and LNM, with enhanced LEF1 and β-catenin expressions seen in metastatic lymph nodes as compared to primary tumors. Additionally, a study by Wang [ 35 ] found an association between increased LEF1 expression and LNM, distant metastasis, advanced TNM staging, and poorer prognosis in colorectal cancer.…”