Mechanisms of epigenetic silencing of the Rassf1a gene during oestrogen-induced breast carcinogenesis in ACI rats

Epigenetic changes include alterations of chromatin structure mediated by methylation of cytosine residues in CpG dinucleotides, modification of histones by acetylation or methylation, or changes in higher-order chromosome structure. This phenomenon can be found in many tumouigenesis, including breast cancer.

Starland-Davenport demonstrated that oestrogen-induced breast cancer in rats is associated with an aberrant DNA methylation and increase in trimethylation of histone H3 at Rassf1a promoter. In this study, significant increase of 5-methyl-2’-deoxycytidine content in Rassf1a gene was recorded after 12 weeks of oestrogen exposure, whereas other promoter regions, such as, p16, Socs1, Cx26, and Cdh1, which are usually hypermethylated in human breast cancer, did not show any statistically meaningful increase of methylation level. Moreover, complete loss of Rassf1a protein and significant decrease of Socs1 protein was recorded, which suggested that epigenetic modification of these genes are associated with compromised expression of those genes. Aside from that, the substantial increase of H3K9me3 and H3K27me3 (trimethylation of histone H3 lysine 9 and 27) was registered at the promoter regions of Rassf1a and Socs1 genes. This suggests that trimethylation of histones can contribute to the oncogenesis of oestrogen-induced breast cancer.

Even though breast cancer is generally recognised as the alteration of BRCA1 and BRCA2 gene, this study revealed that there is a close correlation between epigenetic modification of Rassf1a and oestrogen-induced breast cancer in rat model.

Original research paper from; Starlard-Davenport, A., et al., Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats. Carcinogenesis, 2010. 31(3): p. 376-381.


Beomjun Kim