Biography

I am a molecular oncologist with long experience in chromatin control of transcription in cancer, virus expression and cellular immunology. All of the work in my lab is focused on the BET bromodomains proteins, a family comprised of BRD2, BRD3 and BRD4 in somatic cells, which are important as transcriptional co-regulators.
I was the first to show that BET bromodomain proteins are important for human cancer, with the 1996 demonstration that the activity of BRD2 (then called RING3) is elevated in human acute leukemias (Denis & Green 1996 Genes Dev. 10) and I have been a leader in the field since then. The BET protein field has grown from sixteen papers, when I first published my work, to over 1,300 to date; they have since been implicated in multiple cancer types.
BET proteins are related to the basal transcription factor TAFII250; they bind to acetylated histones through bromodomains, then recruit transcription factors and co-activators/co-repressors to promoter chromatin. Through its association with the SWI/SNF complex, Brd2 helps remodel chromatin to regulate transcription activity. This highly conserved and ubiquitous protein is essential for life; knockout of the gene is lethal in all organisms tested so far (mice, Drosophila, yeast). We have used American Cancer Society and NCI funding to discover that, in mammals, two key targets of Brd2 are the cyclin A locus , which controls cell cycle progression through S phase, and gene targets of the PPARgamma transcription factor, which controls adipogenic transcription. Brd2 is a positive regulator of proliferation but a negative regulator of adipogenesis. In transgenic mice that constitutively express Brd2 in B cells, cyclin A is upregulated and the cell cycle is destabilized, leading to an aggressive non-Hodgkin’s lymphoma. We have also reconstituted the murine immune system with hematopoietic stem cells transduced with lentiviruses for Brd2 overexpression or shRNA knockdown, and learned that Brd2 expression causes a dramatic expansion of the lymphoid compartment and B cell hypersensitivity to mitogens, whereas Brd2 knockdown completely blocks lymphoid development, suggesting that this factor plays a crucial and fundamental role in normal immune biology and the processes of adaptive immunity. These pathways are critical for cancer progression in patients who have chronic, co-morbid metabolic diseases, and consequently inflamed or immune exhausted tumor microenvironments.
Specifically, our recent data have established that BET proteins provide a functional link between abnormal metabolism, inflammation and breast cancer progression. Intriguingly, we have discovered that BET proteins also regulate transcription of immune exhaustion genes, such as PD-1 on human peripheral T cells and PD-L1 on tumor cells in several types of cancer, including triple negative and estrogen receptor positive breast cancer. These discoveries lay out a path for our ongoing work to reveal BET protein regulation of immune evasion and to maximize the efficacy of immuno-oncology therapeutics for breast cancer.