Epigenetic reprogramming of breast cancer cells with oocyte extracts

Molecular Cancer

Research

James E Dixon¹  Michael D Rushton¹  Andrew D Johnson¹  Ramiro Alberio²  Virginie Sottile³  Cinzia Allegrucci⁴  Rajendra Kumari⁵  Sue Watson⁵  Mansi Shah⁶ 

[1] Centre for Genetics and Genomics, School of Biology, Queens Medical Centre, University of Nottingham, NG2 2UH, Nottingham, UK;Centre for Genetics and Genomics, School of Biology, Queens Medical Centre, University of Nottingham, NG2 2UH, Nottingham, UK;School of Biosciences, University of Nottingham, Sutton Bonington Campus, LE12 5RD, Loughborough, UK;Centre for Genetics and Genomics, School of Biology, Queens Medical Centre, University of Nottingham, NG2 2UH, Nottingham, UK;School of Clinical Sciences, Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, University of Nottingham, NG7 2RD, University Park, UK;Centre for Genetics and Genomics, School of Biology, Queens Medical Centre, University of Nottingham, NG2 2UH, Nottingham, UK;School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, LE12 5RD, Loughborough, UK;School of Clinical Sciences, Division of Preclinical Oncology, Queens Medical Centre, University of Nottingham, NG2 2UH, Nottingham, UK;School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, LE12 5RD, Loughborough, UK;

关键词: Tumour Suppressor Gene;    Histone Mark;    Human Mammary Epithelial Cell;    Epigenetic Reprogram;    Amphibian Oocyte;   

DOI  :  10.1186/1476-4598-10-7

 received in 2010-02-22, accepted in 2011-01-13,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundBreast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis.ResultsWe show that breast cancer cells can be directly reprogrammed by amphibian oocyte extracts. The reprogramming effect, after six hours of treatment, in the absence of DNA replication, includes DNA demethylation and removal of repressive histone marks at the promoters of tumour suppressor genes; also, expression of the silenced genes is re-activated in response to treatment. This activity is specific to oocytes as it is not elicited by extracts from ovulated eggs, and is present at very limited levels in extracts from mouse embryonic stem cells. Epigenetic reprogramming in oocyte extracts results in reduction of cancer cell growth under anchorage independent conditions and a reduction in tumour growth in mouse xenografts.ConclusionsThis study presents a new method to investigate tumour reversion by epigenetic reprogramming. After testing extracts from different sources, we found that axolotl oocyte extracts possess superior reprogramming ability, which reverses epigenetic silencing of tumour suppressor genes and tumorigenicity of breast cancer cells in a mouse xenograft model. Therefore this system can be extremely valuable for dissecting the mechanisms involved in tumour suppressor gene silencing and identifying molecular activities capable of arresting tumour growth. These applications can ultimately shed light on the contribution of epigenetic alterations in breast cancer and advance the development of epigenetic therapies.

【 授权许可】

CC BY   
© Allegrucci et al; licensee BioMed Central Ltd. 2011