A team of Northern New England Clinical & Translational Research Network and University of Vermont Cancer Center scientists and physician investigators has been awarded a $9 million, five-year grant from the National Cancer Institute (NCI) to investigate the underlying causes of breast cancer with the goal of identifying new cellular-level targets that could be treated with drugs to prevent the disease or halt its progression.
The principal investigators for the project are Gary Stein, Ph.D., Perelman Professor and chair of the UVM Larner College of Medicine Department of Biochemistry and professor of surgery, and Janet Stein, Ph.D., a professor of biochemistry at the Larner College of Medicine. Gary Stein is the Vermont principal investigator for the Northern New England Clinical & Translational Research Network and Janet Stein is the leader for the Northern New England Clinical & Translational Research Network Pilot Grant Program. They lead a large, collaborative team representing scientific expertise across three colleges at the University of Vermont.
The research will focus on three interrelated projects to determine what goes awry when cell division in healthy breast tissue becomes defective and produces cancer cells. Its focus will be on epigenetics, the instructions that proteins and nucleic acids within a cell’s nucleus give to its genetic code—its DNA—that tell genes to turn on or off. When a cell reproduces, these epigenetic instructions are passed on to newly formed cells, along with the parental cell DNA, its genetic blueprint. If the epigenetic instructions don’t function precisely, cells can become cancerous. The goal is understanding cancer-compromised epigenetic control of genes in breast tumors.
The first project will examine in detail how instructions for the epigenetic regulation of genes—whether they are turned on or off, or poised to turn on—are passed on from a parent cell to its two offspring cells accurately, so there are no defects in the control of its specialized function or its ability to go through cell division in a normal way. The objective is to understand, precisely what are the components, what are the epigenetic factors that remain with the gene during cell division, in order to ensure that you are not going to compromise normal function in the progeny cells.”
The second project focuses on the proteins, called histones, that organize the two-and-a-half yards of DNA within a cell’s nucleus into intricate folds inside a chromosome. If these proteins bind a section of the folded DNA tightly, genes won’t be expressed; if the bond is loose, the genes will be expressed or poised to express. In cancer cells, the ability to modify these proteins is undermined. The project will seek both to chart how the DNA organizing process works and identify drug targets that will restore function of cancer-compromised proteins.
The third project will examine the functioning of a type of long non-coding RNA found in a cell’s nucleus that the research team discovered in an earlier project. It is present only when cells divide, the team found, and is associated with breast cancer, especially in its most aggressive forms, and is not responsive to conventional cancer treatments. Earlier work from the research team showed that, if the activity of this particular type of RNA is blocked, the cancer cell is unable to reproduce and dies. It is a prime drug target.
The Northern New England Clinical & Translational Research Network Translational Research Technology Core was instrumental in securing the grant. These facilities allow researchers to peer into cells and chromosomes and view genes and proteins visually in three dimensions. The work would not be impossible without this highly advanced instrumentation in the Translational Research Technology Core and the world-class expertise behind that technology, which allows identification and visualization of modified genes and gene expression in cancer cells.