Abstract
Luminal B breast cancers (BC) have a more aggressive behavior associated with a higher rate of tumor relapse and worse prognosis compared to luminal A tumors. In this study, we evaluated the involvement of specific epithelial-to-mesenchymal transition- (EMT-) and immune-related pathways in the dissemination of luminal B BC cells. The expression of 42 EMT- and immune-related genes was evaluated in matched sentinel lymph nodes (SLNs) analyzed by the one-step nucleic acid amplification assay (OSNA) and primary tumors of 40 luminal B BC patients by gene array and immunohistochemistry. The results were validated in an independent group of 150 luminal B tumors by immunohistochemistry and immunofluorescence and using gene expression data from 315 luminal B BC patients included in the Metabric dataset. We found that the expression of CXCR4 (p = 3.28E − 02) and CD163 (p = 6.92E − 03) was significantly upregulated in SLNs of recurrent luminal B BC patients. Luminal B primary tumors overexpressing CXCR4 were characterized by an increased expression of vimentin and a high content of CD163-positive macrophages. Bioinformatics analysis confirmed the correlation of CXCR4 with CXCL12, VIM, and CD163 expression and LN involvement. Our results suggest that the upregulation of the CXCR4/CXCL12 pathway and the presence of protumor macrophages in the primary tumor and SLNs sustain the aggressiveness of an important subgroup of luminal B BC.
Highlights
Breast cancer (BC) is a heterogeneous disease, which encompasses distinct subtypes that differ in molecular features, clinical behavior, and response to treatment [1,2,3]
We demonstrated that the overexpression of CXCR4 in luminal B (HER2-negative) BC was significantly associated with LN positivity according to both Mann–Whitney (p = 0 003) and Fisher’s exact test (FET) tests (p = 0 001)
These results suggest that a permissive tumor microenvironment in the primary tumor and sentinel lymph nodes (SLNs), characterized by epithelial-to-mesenchymal transition (EMT) features such as the activation of CXCR4/ CXCL12 axis and the presence of protumor M2 tumor-associated macrophages (TAMs), can sustain the aggressiveness of cancer cells and support their metastatic dissemination in luminal B BC
Summary
Breast cancer (BC) is a heterogeneous disease, which encompasses distinct subtypes that differ in molecular features, clinical behavior, and response to treatment [1,2,3]. Gene expression-based classification identified four major BC molecular subtypes defined as luminal A and B, human epidermal growth factor receptor 2- (HER2-) enriched, and triple negative (TN)/basal-like tumors [1,2,3]. Disease Markers a more aggressive behavior compared to luminal A cancers, showing a pattern of tumor recurrence and prognosis similar to those of HER2-enriched and TN/basal-like cancers [6]. It is well established that cancer cells, moving from primary breast tumor, can reach distant organs and metastasize through both blood and lymphatic vessels [7]. Tumor dissemination through SLNs, which can be rapidly detected through the one-step nucleic acid amplification assay (OSNA), is often driven by the epithelial-to-mesenchymal transition (EMT) process that allows epithelial cells to detach from the surrounding tissue and acquire a mesenchymal phenotype, gaining migratory and invasive abilities [9, 10]
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