Insulin-like growth factor binding protein-3 (IGFBP-3) plays a role in the anti-tumorigenic effects of 5-Aza-2'-deoxycytidine (AZA) in breast cancer cells

Li Zeng, Caroline Jarrett, Keith Brown, Kathleen M Gillespie, Jeffrey M P Holly, Claire M Perks

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Breast cancer progression is associated with loss of estrogen receptor (ER-α), often due to epigenetic silencing. IGFBP genes have consistently been identified among the most common to be aberrantly methylated in tumours. To understand the impact of losing IGFBP-3 tumour expression via DNA methylation, we treated four breast cancer cell lines (MCF-7, T47D, Hs578T and MDA-MB-231) with a DNA methyltransferase inhibitor, 5-Aza-2'-deoxycytidine (AZA) to determine IGFBP-3's role in the effects of AZA on total cell number and survival relative to changes in the ER. AZA induced cell growth inhibition, death and a reduction in the formation of colonies, despite increasing ER-α expression in ER-negative cells but reducing ER-α in ER-positive cells. Regardless of the differential effects on the ER-α, AZA consistently increased the abundance of IGFBP-3 and negating this increase in IGFBP-3 with siRNA reduced the AZA-induced growth inhibition and induction of cell death and virtually negated the AZA-induced inhibition of colony formation. With ER-α positive cells AZA increased the abundance of the tumour suppressor gene, p53 and induced demethylation of the IGFBP-3 promoter, whereas with ER negative cells, AZA epigenetically increased the transcription factor AP2-α, which when silenced prevented the increase in IGFBP-3. IGFBP-3 plays an important role in the anti-tumorigenic effects of AZA on breast cancer cells.

Original languageEnglish
Pages (from-to)2282-95
Number of pages14
JournalExperimental Cell Research
Volume319
Issue number14
DOIs
Publication statusPublished - 15 Aug 2013

Keywords

  • Antimetabolites, Antineoplastic
  • Azacitidine
  • Breast Neoplasms
  • Cell Death
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • DNA Methylation
  • Epigenesis, Genetic
  • Estrogen Receptor alpha
  • Female
  • Gene Silencing
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3
  • MCF-7 Cells
  • RNA, Small Interfering
  • Transcription Factor AP-2
  • Tumor Suppressor Protein p53

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