T regulatory cells (Tregs) are a lineage of lymphocytes involved in immune response suppression that are characterized by the expression of the forkhead box P3 (FOXP3)
transcription factor. Notch pathway regulates FOXP3 transcription in Tregs, but its role in
breast cancer is unknown. We aimed at studying whether Notch pathway regulates FOXP3 expression and Tregs content in
breast cancer, and its association with
luminal breast carcinomas. We analyzed by quantitative Real-Time PCR the
mRNA levels of FOXP3, Notch pathway genes (Notch1, Notch2, Notch4 and Jagged1) and STAT3 in a series of 152
breast carcinomas including
hormone receptor-positive and -negative phenotypes (
luminal and Triple Negative/Basal-like). We also studied the
protein expression of Notch1, STAT3 and FOXP3 by immunohistochemistry. High FOXP3
mRNA levels correlated with larger
tumor size (p=0.010), histological grade 3 (p=0.008) and positive lymph-node status (p=0.031). Also, low levels of Notch pathway genes
mRNA correlated with poor prognostic factors such as larger
tumor size, positive lymph-node status,
tumor phenotype and infiltrating
tumor Tregs. A survival analysis for the patients showed that large
tumor size, histological grade 3, vascular invasion, infiltrating Tregs and low Notch1
mRNA expression were significantly associated with a decreased patients' overall survival (p≤0.05). On a multivariate analysis, high Tregs content (HR=3.00, 95% CI 1.04-8.90, p=0.042) and low Notch1
mRNA levels (HR=3.33, 95% CI 1.02-10.86, p=0.046) were independent markers for overall survival. Our results support that the Notch pathway up-regulation promotes
luminal breast carcinomas, whereas down-regulation correlates with the expression of FOXP3, favors
tumor Tregs infiltration and associates with Triple Negative/Basal-like
tumors.