Functional genomics of triple-negative breast cancer: role of transcription factor Fra-1

Triple-negative breast cancer (TNBC), which is defined merely by a lack of expression of estrogen receptor (ER) and progesterone receptor (PR) as well as the absence of HER2 overexpression, is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Our lab was the first to highlight that Fra-1, belonging to the AP-1 transcription factor family, is overexpressed in TNBC, and that high Fra-1 expression is associated with aggressiveness and poor prognosis of breast cancer (Zhao et al. Cancer Res, 74, 3983-94, 2014). We and others also showed that Fra-1 is a key regulator that drives epithelial–mesenchymal transition (EMT), resulting in increased invasive and metastatic capabilities of tumor cells (Qiao et al. Oncotarget, 6, 7804-14, 2015; Dhillon et al. Oncogene, 34, 4421-4428, 2014). These findings suggest that the Fra-1 protein should be explored as a target for cancer therapy.

The transactivation function of Fra-1 requires associated coregulators and other interacting proteins that function in the Fra-1 complex. Here, the objective is to understand the nature and composition of Fra-1 interacting protein complexes that define its target gene specificity and transcriptional properties. Using newly developed proteomic approaches, we recently identified 124 proteins associate with DNA-bound Fra-1 within the TNBC cell nucleus. We hypothesize that several associated proteins are potential novel Fra-1 coactivators. We are looking for students who are interested to address the following research questions, 1) if the protein candidates coactivate Fra-1 dependent gene expression, and 2) whether depletion of the candidates renders TNBC tumors less aggressive. The main methods to be used include ChIP-seq, Co-immunoprecipitation, qPCR, RNAi, FACS and transfection etc.