Association of Notch pathway down-regulation with Triple Negative/Basal-like breast carcinomas and high tumor-infiltrating FOXP3+ Tregs.
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.
Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), C/Pintor Baeza 12, 03010 Alicante, Spain. Electronic address: fer_om@hotmail.es.
Fernando
F
Ortiz-Martínez
Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), C/Pintor Baeza 12, 03010 Alicante, Spain. Electronic address: biofranse@gmail.com.
Francisco José
FJ
Gutiérrez-Aviñó
Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), C/Pintor Baeza 12, 03010 Alicante, Spain. Electronic address: sanmartin_ele@gva.es.
Elena
E
Sanmartín
Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), C/Pintor Baeza 12, 03010 Alicante, Spain. Electronic address: investigacion_hgua@gva.es.
Eloy
E
Pomares-Navarro
Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), C/Pintor Baeza 12, 03010 Alicante, Spain. Electronic address: cristina.vllb@gmail.com.
Cristina
C
Villalba-Riquelme
Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), C/Pintor Baeza 12, 03010 Alicante, Spain. Electronic address: investigacion_hgua@gva.es.
Araceli
A
García-Martínez
Department of Pathology, Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 87-89, 08041, Barcelona, Spain. Electronic address: elerrma@santpau.cat.
Enrique
E
Lerma
Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), C/Pintor Baeza 12, 03010 Alicante, Spain; Pathology Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain. Electronic address: peiro_glo@gva.es.
Gloria
G
Peiró
D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D015536:Down-Regulation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000072100:Jagged-1 Protein; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor
Breast carcinoma; FOXP3; Notch; STAT3; Tregs; mRNA expression