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

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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.

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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

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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.

Author information

Author notes

  1. Frederic M. Waldman

    Present address: Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA

  2. Aseem Lal

    Present address: Department of Pathology, SPS Apollo Hospitals, Ludhiana, 141003, India

  3. Koei Chin

    Present address: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, 97221, USA

Authors and Affiliations

  1. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, 94143, USA

    Aseem Lal, Sandy DeVries, Koei Chin & Frederic M. Waldman

  2. Department of Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA

    Loretta Chan & Frederic M. Waldman

  3. Department of Medicine and Oncology/Hematology, University of California San Francisco, San Francisco, CA, 94143, USA

    Christopher C. Benz

  4. Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA

    Yunn-Yi Chen

  5. Buck Institute for Research on Aging, Novato, CA, 94945, USA

    Gary K. Scott & Christopher C. Benz

  6. Department of Surgery, Duke University, Durham, NC, 27710, USA

    E. Shelley Hwang

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  1. Aseem Lal
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Corresponding authors

Correspondence to Aseem Lal or E. Shelley Hwang.

Additional information

E. Shelley Hwang and Frederic M. Waldman contributed equally to this study.

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Lal, A., Chan, L., DeVries, S. et al. FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast. Breast Cancer Res Treat 139, 381–390 (2013). https://doi.org/10.1007/s10549-013-2556-4

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  • DOI: https://doi.org/10.1007/s10549-013-2556-4

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