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

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.