Cellular neighbors
For Kornelia Polyak, epigenetics sheds light on the relationship between malignant breast cells and their normal neighbors.
Brown and Kornelia Polyak, MD, PhD, lead Dana-Farber's efforts in epigenetic research. Though they work on different aspects of the cancer puzzle, both have made discoveries about the basic function of cells' growth "control panels."
Polyak has used epigenetics to understand how normal breast cells sometimes incite neighboring cancer cells to grow faster and become more aggressive.
Several years ago, she and her colleagues discovered that genes in the breast's milk duct cells were especially active if a clump of new cancer cells had formed inside the duct. But the DNA within milk duct cells was the same whether or not breast tumor cells were nearby. Clearly, something else had to be responsible for the increase in gene activity.
Polyak reasoned that the answer might lie in methylation differences – namely, that genes in cells surrounding new tumors had lower levels of methylation and, therefore, fewer restrictions on their activity. There were several techniques for checking the methylation state of a cell gene by gene, but Polyak's team was interested in broad-scale patterns that covered the entire human genome of 20,000 to 25,000 genes. They devised a method called methylation specific digital karyotyping (MSDK) that can scan a cell's complete methylation profile; within a few weeks, they could obtain results that would have taken months to complete with conventional methods, if such methods would have worked at all.
Using MSDK, the scientists tested two varieties of cells that line the breast ducts, as well as cells that hold the ducts in place or surround them. They found that in all three types, gene expression was altered by DNA methylation changes not present in normal breast tissue cells.
"Detecting the epigenetic aberrations may be a means of early cancer diagnosis or even predicting cancer risk."
"This was the first demonstration that epigenetic alterations occur in the tumor's 'microenvironment,' the cells that surround the tumor itself," Polyak says. "And it emphasizes the active role that such cells play in cancer formation and growth. These changes in the microenvironment may occur even before breast duct cells undergo genetic changes that cause cancer. Thus, detecting the epigenetic aberrations may be a means of early cancer diagnosis or even predicting cancer risk."
More recently, Polyak has used MSDK and other techniques to investigate how a cancer develops from a single, misguided cell in the epithelial cells that line the milk ducts of the breast. "Some researchers have proposed that epigenetic changes in a stem cell – which has the ability to form several different types of cells in the epithelium – trigger the cancer process," she says.
To begin exploring this issue, Polyak and her colleagues mapped methylation patterns in stem cells and their "descendants" – the more specialized cells that form different layers of the epithelium. They found that each cell type had a distinctive pattern, and that the patterns persisted in breast tumor tissue. Such profiles offer a way to distinguish different varieties of breast cancer, predict the course of the disease, and determine how it should be treated.
"These findings," Polyak remarks, "shed new light on cells that give rise to the various components of the epithelium, and provide an avenue for learning how they specialize [or 'differentiate'] to take on different roles, and how they're related to the cells that begin the cancer process."
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