Breast Cancer Research and Treatment

, Volume 158, Issue 1, pp 21–28 | Cite as

Stromal cells in phyllodes tumors of the breast are enriched for EZH2 and stem cell marker expression

  • Yanhong Zhang
  • Adam L. Liss
  • Eugene Chung
  • Lori J. Pierce
  • Celina G. KleerEmail author
Preclinical study


Phyllodes tumors (PTs) of the breast are fibroepithelial neoplasms with stromal hypercellularity, which is the basis for their classification as benign, borderline, and malignant. The histologic diagnosis of PTs is often difficult, and the pathological features may not always predict clinical behavior. The pathobiology of PT remains poorly understood. Enhancer of Zeste 2 (EZH2) epigenetically regulates cell-type identity, cellular differentiation, and breast cancer stem cells. EZH2 exerts oncogenic functions in breast cancer and is associated with metastasis. We hypothesized that in PTs, EZH2 and the stem cell marker ALDH1 may be expressed in stromal cells and may be associated with their degree of differentiation. Forty PTs were histologically characterized at our institution following the World Health Organization criteria. We investigated the expression of EZH2 and ALDH1 by immunohistochemistry and recorded as percentage of positive epithelial and stromal cells. EZH2 was positive when over 10 % of cells exhibited nuclear staining; ALDH1 was positive when over 5 % of cells had cytoplasmic staining. Of the 40 PTs, 24 (60 %) were histologically benign, 8 (20 %) borderline, and 8 (20 %) malignant. Stromal EZH2 was significantly associated with the diagnosis of malignant PT, as it was detected in 1 of 24 (4 %) benign, 3 of 8 (37.5 %) borderline, and 5 of 8 (62.5 %) malignant tumors. Stromal EZH2 was significantly associated with stromal overgrowth (p = 0.01), atypia (p = 0.01), hypercellularity (p = 0.01), and mitoses (p = 0.02), all features of malignant PT. Stromal EZH2 and ALDH1 were significantly associated with grade of PT (p = 0.01 and p < 0.05 respectively). In conclusion, EZH2 and ALDH1 expression in the stroma of PT may mark malignant progression and may be helpful to distinguish histologically benign from borderline and malignant tumors in challenging cases. Our study also suggests that PTs contain mesenchymal stem cells, shedding light into the pathogenesis of these tumors.


EZH2 ALDH1 Phyllodes tumors Breast cancer Stromal cells Stem cell 



This work was supported by NIH Grants R01 CA107469 and CA125577, and the National Institutes of Health through the University of Michigan’s Cancer Center Support Grant (5 P30 CA46592).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yanhong Zhang
    • 1
  • Adam L. Liss
    • 2
  • Eugene Chung
    • 2
  • Lori J. Pierce
    • 2
    • 4
  • Celina G. Kleer
    • 3
    • 4
    Email author
  1. 1.Department of PathologyUniversity of California DavisSacramentoUSA
  2. 2.Departments of Radiation OncologyUniversity of MichiganAnn ArborUSA
  3. 3.Department of PathologyUniversity of MichiganAnn ArborUSA
  4. 4.Comprehensive Cancer CenterUniversity of MichiganAnn ArborUSA

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