Julie Douglas
Associate Professor of Human Genetics
Simple life, complex disease
The bucolic countryside of eastern Pennsylvania may not seem a likely setting for modern genetics research, but to Julie Douglas, it's ideal. What draws her there is not the pastoral scenery, but the plain-living people who tend the fields of Lancaster County. In the Old Order Amish, Douglas has found a study population that can help her home in on genes associated with breast density, one of the least understood breast cancer risk factors.
"Women who have dense tissue in more than 75 percent of their breasts are at a four- to six-fold increased risk of breast cancer, compared to women with little or no breast density," says Douglas. Only aging and mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are stronger risk factors, yet little is known about exactly why having dense tissue increases the likelihood of breast cancer.
What is known is that both breast density and breast cancer risk vary with age and reproductive and menstrual history, and that while genetic factors are thought to account for almost half the variation in breast density among women, non-genetic factors, such as the use of contraceptives and hormone therapy, also can affect density. By studying Amish women, who eschew contraceptives and rarely use hormone therapy, Douglas can minimize non-genetic effects and zero in on genetic factors. In one recent study of this population, her research group was able to show for the first time that breast density and other inherited risk factors share some of the same genetic underpinnings.
"Specifically, we found that the genetic factors that influence the dense areas of the breast overlap with some of the genetic factors that influence how many children a woman bears," says Douglas. Scientists have known for decades that there's some connection among number of live births, breast density and breast cancer risk, but they haven't understood exactly how everything ties together.
One suggested mechanism has to do with changes that occur in breast tissue during pregnancy. The cells making up the tissue differentiate (become specialized), which makes them less capable of multiplying.
"With subsequent pregnancies, the breast cells differentiate further, resulting in a smaller and smaller population of cells that are capable of multiplying and becoming cancerous," says Douglas. "While this process may partially explain the relationship, our research has revealed another mechanism---apart from the differentiation process---by which breast density and number of live births may be related, and we were able to discover that only because we were studying such a unique population. Since the Amish forbid the use of contraceptives, the typical socio-cultural factors that would influence how many children a woman bears are minimized in our study."
Identifying the actual genes that influence breast density is Douglas's ultimate goal, and toward that end her team has recruited more than 1,400 Amish women and their relatives for a large-scale study. The point is to identify particular segments of DNA that are shared by relatives whose breast density is similar and eventually to pinpoint genes within those regions that directly affect breast density.
Again, the Amish, with their close family ties and meticulous genealogical records, are an excellent fit. Though their lifestyle may be simple and their communities insulated, they're helping Douglas unravel the complexities of a disease that affects women throughout the world.
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