Metastasis, in which cells detach from a primary tumor and establish themselves in a new site, is strongly associated with poorer clinical outcomes. The ability to suppress metastasis will require a better understanding of its mechanisms. An important driving force in metastasis of solid tumors is the epithelial to mesenchymal transition (EMT), which involves the loss of cell-cell adhesion and cell polarity, and the acquisition of migratory and invasive properties. The EMT is similar to developmental processes that entail epigenetic reprogramming. In vertebrates cytosine methylation functions to suppress transcription initiation: promoter methylation is associated with transcriptional silence. Demethylation of cytosines occurs during the EMT, but the mechanism of this demethylation, and its causal relationship with the EMT, is not yet known. Activation-induced cytidine deaminase (AID) has been found to mediate active D-demethylation of cytosine residues in vivo. Recent evidence implicates AID in cytosine D (deamination driven)-demethylation during developmental processes, and in particular in demethylation of specific promoters during nuclear reprogramming. We have found that AID expression is necessary for breast cancer cells to undergo the EMT, prompting the hypothesis that AID is a driver of metastasis through its ability to D-demethylate promoters of genes that mediate the EMT. Our hypothesis predicts that there is an association between AID binding and cytosine D-demethylation during the EMT, and that expression of genes critical for the EMT is regulated by AID. We propose to test these predictions and develop data on the roles and relationships of AID, cytosine methylation before and during the EMT, and gene expression in breast cancer cells. These studies will produce datasets for AID binding and cytosine methylation that will advance understanding of their roles and relationship in cancer cells and in the EMT, and open new avenues for discovery/development of therapeutic inhibitors of AID for the prevention of metastasis.

Public Health Relevance

Cancer is a disease in which cells abnormally multiply and spread. This is a proposal to investigate a newly discovered mechanism that may allow cancer cells to change in ways that make it possible for them to spread (metastasize). A better understanding of this process may lead to new ways to treat cancer and prevent metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Subcommittee G - Education (NCI)
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Wali, Anil
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Children's Hospital & Res Ctr at Oakland
United States
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Montamat-Sicotte, Damien; Litzler, Ludivine C; Abreu, Cecilia et al. (2015) HSP90 inhibitors decrease AID levels and activity in mice and in human cells. Eur J Immunol 45:2365-76
Munoz, Denise P; Kawahara, Misako; Yannone, Steven M (2013) An autonomous chromatin/DNA-PK mechanism for localized DNA damage signaling in mammalian cells. Nucleic Acids Res 41:2894-906
Muñoz, Denise P; Lee, Elbert L; Takayama, Sachiko et al. (2013) Activation-induced cytidine deaminase (AID) is necessary for the epithelial-mesenchymal transition in mammary epithelial cells. Proc Natl Acad Sci U S A 110:E2977-86