Identification of Transcription Factors Critical for the Growth and Treatment of Breast Cancer
RNA transcription profiling has enabled breast tumors to be defined in distinct subtypes (basal, luminal and HER2) which possess unique prognoses and treatment options. Key regulators, such as estrogen receptor alpha and HER2, have been identified for the luminal and HER2 subtypes, while master regulators for the basal tumors remain unknown. Recent studies have shown inherent distinctions between basal and luminal breast cancers at the transcriptional level. Since transcription factors (TFs) are able to directly regulate RNA transcription of multiple genes by binding cis-regulatory elements of DNA, resulting in the coordinated response of an entire gene set, TFs are promising candidates as master regulators of basal breast cancer.
We hypothesize that specific TFs regulate the transcriptional profile related to basal breast cancer and the aggressive proliferation associated it. To test this hypothesis, we are using three independent screening approaches to identify specific TFs critical for the regulation of basal breast cancer. First, we are identifying TF binding motifs which are over-represented among promoters of genes over-expressed in basal tumors. Second, we are querying breast cancer protein to identify TFs which bind labeled DNA probes in basal cell lines to a higher degree than in luminal cell lines. Finally, due to the open chromatin conformations characteristic of the regulatory regions bound by TFs, we are using formaldehyde-assisted isolation of regulatory elements (FAIRE) to identify regions of open chromatin in basal cells as well as the TFs which bind these regions. Candidate TFs identified through these screening techniques will be selected for further studies to define their roles in the regulation of basal gene expression and to ascertain which TFs are critical for the proliferation of basal breast cancer cells. Identifying TFs which act as master regulators of the basal subtype will increase our understanding of the biology of basal-like tumors and, more importantly, will identify potential targets for future therapeutic strageties to treat this aggressive type of breast cancer.
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Lab members working on this project: