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Breast Cancer Research and Treatment

, Volume 139, Issue 2, pp 381–390 | Cite as

FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast

  • Aseem LalEmail author
  • Loretta Chan
  • Sandy DeVries
  • Koei Chin
  • Gary K. Scott
  • Christopher C. Benz
  • Yunn-Yi Chen
  • Frederic M. Waldman
  • E. Shelley HwangEmail author
Preclinical study

Abstract

FOXP3-expressing T regulatory lymphocytes (Tregs) have been described as putative mediators of immune tolerance, and thus facilitators of tumor growth. When found in association with various malignancies, Tregs are generally markers of poor clinical outcome. However, it is unknown whether they are also associated with cancer progression. We evaluated quantitative FOXP3 expression in lymphocytes as well as in epithelial cells in a set of thirty-two breast tumors with synchronous normal epithelium, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) components. Tumors were stained for FOXP3 and CD3 expression and Tregs quantified by determining the ratio of colocalized FOXP3 and CD3 relative to 1) total CD3-expressing lymphocytes and 2) to FOXP3-expressing epithelial cells. The median proportion of FOXP3-expressing CD3 cells significantly increased with malignant progression from normal to DCIS to IDC components (0.005, 0.019 and 0.030, respectively; p ≤ 0.0001 for normal vs. IDC and p = 0.004 for DCIS vs. IDC). The median intensity of epithelial FOXP3 expression was also increased with invasive progression and most markedly augmented between normal and DCIS components (0.130 vs. 0.175, p ≤ 0.0001). Both Treg infiltration and epithelial FOXP3 expression were higher in grade 3 vs. grade 1 tumors (p = 0.014 for Tregs, p = 0.038 for epithelial FOXP3), but did not vary significantly with hormone receptor status, size of invasive tumor, lymph node status, or disease stage. Notably, Treg infiltration significantly correlated with epithelial up-regulation of FOXP3 expression (p = 0.013 for normal, p = 0.001 for IDC). These findings implicate both Treg infiltration and up-regulated epithelial FOXP3 expression in breast cancer progression.

Keywords

FOXP3 Lymphocytes Epithelium Breast cancer Ductal carcinoma in situ 

Abbreviations

DAB

3,3′-Diaminobenzidine

DCIS

Ductal carcinoma in situ

ER

Estrogen receptor

FISH

Fluorescent in situ hybridization

FOXP3

Forkhead transcription factor 3

HER2

Human epidermal growth factor receptor 2

IDC

Invasive ductal carcinoma

IHC

Immunohistochemistry

PR

Progesterone receptor

Treg

T regulatory lymphocyte

Notes

Acknowledgments

We wish to thank Tissue Core and Immunohistochemistry Core at the UCSF Hilen Diller Family Comprehensive Cancer Center and the Breast Oncology Program for their expert assistance with this study. We also thank Bay Area Breast Cancer SPORE (Specialized Program of Research Excellence) P50 CA58207, U24 CA143858, and R21 CA155679 and acknowledge partial research support from Merck & Co., Inc.

Supplementary material

10549_2013_2556_MOESM1_ESM.pptx (129 kb)
Supplementary material 1 (PPTX 130 kb)
10549_2013_2556_MOESM2_ESM.docx (14 kb)
Supplementary material 2 (DOCX 14 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Aseem Lal
    • 1
    • 8
    Email author
  • Loretta Chan
    • 2
  • Sandy DeVries
    • 1
  • Koei Chin
    • 1
    • 9
  • Gary K. Scott
    • 5
  • Christopher C. Benz
    • 3
    • 5
  • Yunn-Yi Chen
    • 4
  • Frederic M. Waldman
    • 1
    • 2
    • 6
  • E. Shelley Hwang
    • 7
    Email author
  1. 1.Department of Laboratory MedicineUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Department of Cancer CenterUniversity of California San FranciscoSan FranciscoUSA
  3. 3.Department of Medicine and Oncology/HematologyUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Department of PathologyUniversity of California San FranciscoSan FranciscoUSA
  5. 5.Buck Institute for Research on AgingNovatoUSA
  6. 6.Quest Diagnostics Nichols InstituteSan Juan CapistranoUSA
  7. 7.Department of SurgeryDuke UniversityDurhamUSA
  8. 8.Department of PathologySPS Apollo HospitalsLudhianaIndia
  9. 9.Department of Biomedical EngineeringOregon Health and Science UniversityPortlandUSA

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