Seeking switches
Myles Brown uses epigenetics to explore how the growth of normal and cancerous breast cells is governed.
Genes are often described as blueprints – plans for assembling proteins out of amino acids. In fact, however, only a small portion of each gene contains the DNA code for a specific protein. The vast majority of genetic territory consists of stretches of DNA that are blueprint-free. Portions of these areas may be remnants of obsolete genes or are involved in holding the gene's three-dimensional shape. Other portions, known as regulatory regions, are the "touch pads" where genes are turned on and off.
For Myles Brown, these switches provide clues to understanding how normal breast cells and their malignant cousins are stimulated to grow.
In 2006, Brown and his colleagues provided the most detailed picture yet of how the estrogen receptor – the spark plug of cell proliferation in most breast cancers – operates the cell's growth machinery. The receptor, called ER, is a cup-shaped protein in the cell nucleus. When an estrogen molecule lands in it, the ER binds to the regulatory regions of the cell's key genes, prompting them to initiate cell growth and division. But where these regions are located, and how many of them there are, has, with a few exceptions, been a mystery.
To find them, Brown's team used a novel procedure called chip-on-chip. They first isolated the regions of genes that take orders from the ER, then placed these pieces of DNA on "microarray chips" containing the entire human genome sequence. This allowed the investigators to identify all the points in the genome where ER binding takes place.
They discovered that about 1,000 genes were influenced by the ER, far more than anyone had known. Since most genes have more than one control region, the number of such regions tweaked by the ER was even greater. Brown dubbed the new atlas of binding sites the "estrogen receptor cistrome" ("cis" referring to a regulatory region, "ome" to the collection).
"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. Comparing the ER binding sites of hormone-dependent and -independent breast cancers will make it possible to identify new targets for treatment of advanced tumors."
Earlier this year, Brown published a study on another actor in the cell's epigenetic machinery, a protein called FoxA1. He found that methylation patterns attract FoxA1 to specific sites on the chromatin, altering the chromatin's structure and influencing which genes get translated into proteins. That, in turn, determines what role the cell will play in the body.
"It's clear we have much to learn about all the elements that play a role in gene activation, or expression," Brown says. "With each study, the picture becomes a little clearer."
