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

Athena Davenport, Volodymyr P. Tryndyak, Smitha R. James, Adam R. Karpf, John R. Latendresse, Frederick A. Beland, Igor P. Pogribny

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Breast cancer, the most common malignancy in women, emerges through a multistep process, encompassing the progressive sequential evolution of morphologically distinct stages from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma and metastasis. The success of treatment of breast cancer could be greatly improved by the detection at early stages of cancer. In the present study, we investigated the underlying molecular mechanisms involved in breast carcinogenesis in Augustus and Copenhagen-Irish female rats, a cross between the ACI strains, induced by continuous exposure to 17β-estradiol. The results of our study demonstrate that early stages of estrogen-induced breast carcinogenesis are characterized by altered global DNA methylation, aberrant expression of proteins responsible for the proper maintenance of DNA methylation pattern and epigenetic silencing of the critical Rassf1a (Rasassociation domain family 1, isoform A) tumor suppressor gene. Interestingly, transcriptional repression of the Rassf1a gene in mammary glands during early stages of breast carcinogenesis was associated with an increase in trimethylation of histones H3 lysine 9 and H3 lysine 27 and de novo CpG island methylation and at the Rassf1a promoter and first exon. In conclusion, we demonstrate that epigenetic alterations precede formation of preneoplastic lesions indicating the significance of epigenetic events in induction of oncogenic pathways in early stages of carcinogenesis.

Original languageEnglish (US)
Pages (from-to)376-381
Number of pages6
JournalCarcinogenesis
Volume31
Issue number3
DOIs
StatePublished - Mar 1 2010
Externally publishedYes

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Inbred ACI Rats
Epigenomics
Protein Isoforms
Estrogens
Carcinogenesis
Breast
DNA Methylation
Genes
Lysine
Breast Neoplasms
CpG Islands
Carcinoma in Situ
Human Mammary Glands
Tumor Suppressor Genes
Histones
Methylation
Hyperplasia
Estradiol
Exons
Neoplasms

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Davenport, A., Tryndyak, V. P., James, S. R., Karpf, A. R., Latendresse, J. R., Beland, F. A., & Pogribny, I. P. (2010). Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats. Carcinogenesis, 31(3), 376-381. https://doi.org/10.1093/carcin/bgp304

Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats. / Davenport, Athena; Tryndyak, Volodymyr P.; James, Smitha R.; Karpf, Adam R.; Latendresse, John R.; Beland, Frederick A.; Pogribny, Igor P.

In: Carcinogenesis, Vol. 31, No. 3, 01.03.2010, p. 376-381.

Research output: Contribution to journalArticle

Davenport, A, Tryndyak, VP, James, SR, Karpf, AR, Latendresse, JR, Beland, FA & Pogribny, IP 2010, 'Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats', Carcinogenesis, vol. 31, no. 3, pp. 376-381. https://doi.org/10.1093/carcin/bgp304
Davenport, Athena ; Tryndyak, Volodymyr P. ; James, Smitha R. ; Karpf, Adam R. ; Latendresse, John R. ; Beland, Frederick A. ; Pogribny, Igor P. / Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats. In: Carcinogenesis. 2010 ; Vol. 31, No. 3. pp. 376-381.
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