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 language | English |
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Article number | 10.1016/j.yexcr.2013.06.011 |
Pages (from-to) | 2282-2295 |
Number of pages | 14 |
Journal | Experimental Cell Research |
Volume | 319 |
Issue number | 14 |
Early online date | 26 Jun 2013 |
DOIs | |
Publication status | Published - 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