DNMT3b Mediated Hypermethylator Phenotype in Breast Cancer: Mechanism and Role in Chemotherapy

 

Trainee:

Runinder "Rupan" Sandhu

Rupan

Research Mentor:

Dr. William Coleman, PhD

Coleman

Clinical Co-Mentor;

Dr. Chad Livasy, MD

Livasy
Project Description:

Investigation of the molecular signatures of primary human breast cancers has identified distinct subtypes that include the basal-like subtype, which is aggressive, poorly differentiated, associated with poor clinical outcomes, and contribute disproportionately to breast cancer mortality. These cancers are associated with a high likelihood of relapse, and lack targeted therapeutic approaches. Recent studies from our laboratory found that most basal-like breast cancers express a hypermethylation defect that involves hyperactivity of the DNA methylation machinery and overexpression of DNA methyltransferase 3b (DNMT3b).

We hypothesize that the unique clinical features of basal-like breast cancers may be a direct consequence of aberrant gene expression patterns resulting from methylation-dependent gene silencing events. The mechanisms that govern dysregulation of DNMT3b in breast cancer are unknown. However, studies in other tumor systems suggest strongly that alterations in regulatory microRNAs can lead to overexpression of DNMT3b. The main objective of my project is to understand and characterize the contribution of DNMT3b to the biology and clinical outcome of basal-like breast cancers and to elucidate the role of microRNAs in dysregulation of DNMT3b expression among these cancers.

To test our hypothesis and address our objective, we employ an experimental model of (i) human basal-like breast cancer based on well characterized hypermethylator cell lines that exhibit DNMT3b hyperactivity, and (ii) primary human breast cancers of known molecular classification. Using the cell line based model, we will characterize the mechanistic role of DNMT3b in the expression of hypermethylation defect, contribution of DNMT3b overexpression to sensitivity to chemotherapeutics, and the role of microRNAs in the expression of hypermethylation defect. Utilizing primary breast cancers, we will analyze the mechanisms that govern the hypermethylation defect in basal-like breast cancer by characterizing the differential expression of microRNAs in different molecular classes of primary human breast cancers.