Prognostic Role of Tumor-Infiltrating FOXP3+ Tregs, SKP2, p21 and p27 in Immunophenotypes of Breast Carcinoma
Gloria Peiro, Fernando Ortiz-Martinez, Daniel Giner, Francisco J Gutierrez-Avino, F Ignacio Aranda, Enrique Lerma, Encarna Adrover, Jose Sanchez-Paya, Jose M Sempere-Ortells. Hospital General Universitari, Alacant, Spain; Hospital de La Santa Creu i Sant Pau, Barcelona, Spain; Universitat d'Alacant, Alacant, Spain
Background: The X-linked gene FOXP3 (Xp11.23) is a member of the forkhead family of transcription factors that plays a key role in the immune suppressive function of regulatory T-cells (Tregs). Recently, it has been identified as a tumor suppressor that regulates the transcription activity of oncogenes and tumor suppressor genes. The aim of our study was to evaluate the presence of FOXP3+ Tregs in tumor microenvironment of breast carcinoma (BC) and to correlate the results with the tumor expression of SKP2, p21 and p27; and patient's outcome.
Design: We performed an immunohistochemical (IHC) study of FOXP3, SKP2, p21 and p27 on paraffin-embedded tissue microarrays (1mm diameter cores) containing 372 BC, stratified by immunophenotypes: 24% Luminal A and B (ER/PR+, HER2-), 42% HER2+ (≥30% cells 3+ by IHC and/or FISH/CISH amplification), and 34% TN/basal-like (ER/PR/HER2- +/-CK5/6+/-EGFR). FOXP3+ cells within the tumor and/or immediately adjacent stroma were counted in 3 high power fields (HPF) (x400). Further, the average of positive tumor nuclei (SKP2, p21 and p27) was recorded. The correlations between IHC results, clinicopathological factors and outcome were analyzed.
Results: Median patients' age was 56 years (range 23-89 years) with a median follow-up of 93 months (range 6-371 months). There was a significant correlation between the high number of Tregs (median threshold ≥15 FOXP3+ cells) (27%) and tumors of TN/basal-like phenotype (36%), grade 3 (37%), with necrosis (40%), positive lymph-node status (34%), SKP2 overexpression (45%), and loss of p21 (29%) and p27 (36%) (all p≤0.046). Neither Tregs content nor nuclear p21 and p27 expression showed prognostic significance (all p=ns), whereas SKP2 oncogene overexpression correlated with shorter overall survival (79% vs 69%: p=0.044) (Kaplan-Meier; log rank test).
Conclusions: Our study suggests that FOXP3+ Tregs are markers of aggressive BC, and that might be important for the design of immunotherapy based clinical protocols. The role of FOXP3 as a tumor suppressor is supported by the loss of p21 and p27 and the increased SKP2 oncogene expression in tumor cells, the latter being related with poor prognosis.
Supported by Grants FIS 10/00082, AP-172/10, FCVI-HGUA (2010/PC-04 and 2011/PC-03)
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 30, Wednesday Afternoon