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. 2007 Mar;102(1):19-30. doi: 10.1007/s10549-006-9314-9. Epub 2006 Aug 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Down-Regulation
  • Female
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mice, SCID
  • Microtubule-Associated Proteins / antagonists & inhibitors*
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Transplantation
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-ets / antagonists & inhibitors
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / physiology*
  • RNA, Messenger / analysis
  • RNA, Small Interfering / physiology
  • Survivin
  • Transplantation, Heterologous

Substances

  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-ets
  • RNA, Messenger
  • RNA, Small Interfering
  • SPDEF protein, human
  • Survivin