Abstract
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.
Highlights
Breast cancer is a disease characterised by both genetic and epigenetic alterations
We have previously shown that oocytes of two amphibian species (Xenopus laevis and Ambystoma mexicanum or axolotl) are able to induce chromatin remodelling in somatic cells [21,23], and we tested whether extracts made from prophase oocytes could alter epigenetic marks of cancer cells
Our previous work shows that chromatin remodelling occurs within 3 to 6 hours when fibroblasts are incubated in oocyte extracts [21,23], so we chose the longest time point to assess reprogramming of tumour
Summary
Breast 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. Expression of proto-oncogenes and tumour suppressor genes controls normal cell function, and misregulation of these genes by both genetic and epigenetic alterations is at the origin of cancer [1,2]. Abnormal epigenetic regulation of genes regulating the cell cycle, apoptosis, DNA repair, cell adhesion and signalling leads to tumour formation, its progression, and drug resistance [3]. Epigenetic alterations prevail over genetic abnormalities in initial stages of breast tumour development. Methylation of several homeobox genes is observed in ductal carcinoma in situ and stage I breast tumours [6]
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