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Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo

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Abstract

Previous studies using immunohistochemistry suggest that loss of the expression of the prostate-derived Ets transcription factor (PDEF) is a strong indicator for cancer cell malignancy. However, the underlying mechanism for this has not been well elucidated. We determined the role of PDEF in breast cancer cell growth and tumor formation using a series of experiments including Western blotting, promoter-luciferase reporter assay, RNA interference technology and a mouse xenograft model. We also determined the relationship between PDEF expression in human breast tumor specimen and cancer patient survivability. These studies revealed that PDEF expression is inversely associated with survivin expression and breast cancer cell xenograft tumor formation. PDEF-specific shRNA-mediated silencing of PDEF expression resulted in the upregulation of survivin expression in MCF-7 cells, which was associated with increased cell growth and resistance to drug-induced DNA fragmentation (apoptosis). In contrast, survivin-specific siRNA-mediated silencing of survivin expression decreased MCF-7 cell growth. Ectopic expression of PDEF inhibited both survivin promoter activity and endogenous survivin expression. Importantly, shRNA-mediated silencing of PDEF expression in MCF-7 breast cancer cells enhanced survivin expression and xenograft tumor formation in vivo. Furthermore, loss of PDEF expression in breast cancer tissues tends to be associated with unfavorable prognosis. These studies provide new information for the role of PDEF and survivin in breast cancer cell growth and tumor formation.

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Abbreviations

PDEF/hPSE:

Prostate derived Ets transcription factor/human prostate-specific Ets

IAP:

Inhibitor of apoptosis

SCID:

Severe combined immunodeficiency

ShRNA:

Small hairpin RNA

GAPDH:

Glyceraldehydes 3-phosphate dehydrogenase

RT-PCR:

Reverse transcription-mediated polymerase chain reaction

SD:

Standard deviation

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Acknowledgements

We would like to thank Dr. Brian Bundy for helping with the statistical analyses of the experimental data in this study, Dr. Stephen Edge for clinical information and Dr. Ashwani Sood for his generous helping in the study. This work was sponsored in part by NIH R01 Grants (CA109481), The Susan G. Komen Breast Cancer Foundation (BCTR63806) and Grants from Concern Foundation (Beverly Hill, CA) to FL, and shared resources of an NCI Comprehensive Cancer Center Support Grant (CA16056) to Roswell Park Cancer Institute.

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Authors and Affiliations

  1. Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Street, Buffalo, NY, 14263, USA

    Ali Ghadersohi, Dalin Pan & Fengzhi Li

  2. Department of Pathology, Roswell Park Cancer Institute, Elm and Carlton Street, Buffalo, NY, 14263, USA

    David G. Hicks & Janet S. Winston

  3. Department of Structural Biology, Hauptman Woodward Medical Research Institute, Buffalo, NY, 14203, USA

    Zahra Fayazi

  4. Cancer Institute and School of Life Science & Technology, Tongji University, Shanghai, 200090, China

    Fengzhi Li

Authors
  1. Ali Ghadersohi
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  2. Dalin Pan
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  3. Zahra Fayazi
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  4. David G. Hicks
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  5. Janet S. Winston
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  6. Fengzhi Li
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Correspondence to Fengzhi Li.

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Ghadersohi, A., Pan, D., Fayazi, Z. et al. Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo. Breast Cancer Res Treat 102, 19–30 (2007). https://doi.org/10.1007/s10549-006-9314-9

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  • DOI: https://doi.org/10.1007/s10549-006-9314-9

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