Lurking in unexplored regions of the human genome are thousands of previously unknown on/off switches that may influence how the growth of breast cancer is driven by estrogen, new research by Dana-Farber Cancer Institute researchers has revealed.
In the October issue of Nature Genetics, the investigators present the first complete map of the molecular "control panels" -- stretches of DNA that turn genes on and off -- operated by the cells' estrogen receptor, the master regulator of cell growth in the most common form of breast cancer. The map, which includes thousands of such control regions, provides scientists with a new tool for understanding how genes are regulated, and may eventually help doctors match patients with treatments that are most likely to be effective for them and overcome the problem of resistance to current hormone therapies, the study authors say.
The estrogen receptor (ER) is an intricate protein net in the nucleus of breast cancer cells. When the receptor snares an estrogen molecule, it sets in motion a cascade of activity among genes involved in cell growth and division. In many breast tumors, cells have an unusually large number of ERs, so they proliferate rapidly in the presence of estrogen. Drugs that block the ER, such as tamoxifen and fulvestrant, are often able to stop or slow the growth of these estrogen-driven tumors.
"For the most part, the sequence of steps between the activation of the estrogen receptor and the beginning of tumor cell division has been unclear. We've known of only a handful of the portions of genes that bind to the ER -- the so-called control regions that activate or deactivate the genes," says Dana-Farber's Myles Brown, MD, the senior author of the new study. "With this project we've located all of them, and found there are thousands more than were previously known." Since most genes have more than one control region, the map points to about 1,000 genes influenced, to some degree, by the ER.
The binding-site map was compiled with a novel two-step procedure called ChIP-on-chip. Researchers first used a technique called chromatin immunoprecipitation (ChIP) to purify the regions of genes that take orders from the ER. They then placed these pieces of DNA on "microarray chips" containing the entire human genome sequence. This allowed the researchers to identify all the points in the genome where binding with the ER takes place.
The researchers coined the word "cistrome" to describe the map they had produced -- an atlas of all gene segments influenced by the ER. "cis" refers to a DNA segment that regulates a gene's activity in response to a signal from outside the gene (while "trans" refers to a factor that acts on DNA); and "ome" -- from the Greek word for manager -- refers to the full set of such segments, as "genome" refers to all the genes within human cells.
The map contains many surprises, the study authors say. For one, the majority of binding sites within the cistrome are often very far from the portions of the genes that contain the blueprints for proteins. This overturns the commonly held notion that the ER might favor sites close to the protein-coding regions of genes.
"More than 70 percent of breast cancers are ER-positive, meaning their growth is driven by estrogen," Brown says, "and the estrogen receptor is the most important target for therapy for these tumors. Knowing the complete set of ER binding sites gives us a new resource for understanding the role of estrogen in breast cancer. By identifying genes associated with the ER in breast tumors, it opens up previously unexplored regions of the genome involved in the estrogen-dependence of breast cancer."
The knowledge may one day help researchers and physicians determine which treatments are likely to work best in individual patients and restore the potency of cancer drugs to which patients have become resistant, added Brown, who is also a professor of medicine at Harvard Medical School.
The study was supported by grants from the Claudia Adams Barr Program in Innovative Basic Cancer Research, the National Institutes of Health, the Department of Defense Breast Cancer Research Program, the Fondation Recherche Medicale, and the Susan G. Komen Breast Cancer Foundation.
The lead author of the project is Jason Carroll, PhD, of Dana-Farber. Co-authors include Clifford Meyer, Jun Song, PhD, Wei Li, Timothy Geistlinger, PhD, Jerome Eeckhoute, PhD, Erika Krasnickas Keeton, PhD, Kirsten Fertuck, PhD, Giles Hall, Qianben Wang, MD, PhD, Edward Fox, PhD, Pamela Silver, PhD, and X. Shirley Liu, PhD, of Dana-Farber and Harvard Medical School; Alexander Brodsky, PhD, of Brown University; and Thomas Gingeras, PhD, Stefan Bekiranov, PhD, and Victor Sementchenko, PhD, of Affymetrix of Santa Clara, Calif.
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