In those genetically predisposed, ’developmental reprogramming’ could explain cancer risk

Researchers at The University of Texas M. D. Anderson Cancer Center may have uncovered the reason why some people who are genetically predisposed to hormone-dependent cancers develop the disease as an adult, while others who are similarly susceptible don’t.

In a study to be published on-line in the Proceedings of the National Academy of Sciences (PNAS) the week of May 30, 2005, they show, for the first time, that exposure to a pharmaceutical estrogen during fetal development can permanently “reprogram” tissue in a way that determines whether tumors will develop in adulthood.

While the study was conducted with rats that are susceptible to benign uterine tumors, and the compound used was diethylstilbestrol (DES), a banned estrogenic anti-miscarriage drug, the researchers say their conclusions likely have relevance for humans who inherit defective tumor suppressor genes that make them susceptible to a number of different cancers.

It could explain, for example, why some women who inherited BRCA1/2 gene defects develop breast cancer as adults while other women with the same genes remain disease-free, they say. “The kind of developmental reprogramming we see from this work could represent an important determinate of risk in people genetically susceptible to hormone-dependent tumors, such as uterine, breast and prostate cancer,” says the study’s principal investigator, Cheryl Walker, Ph.D., a professor in the Department of Carcinogenesis. “It suggests that for gene-environmental interactions, the timing of the exposure may be critical, and it may happen much earlier than anyone ever suspected,” she says.

While more work is needed to make the case that human cancer results in the same way, “we need to open our eyes to the notion that cancer that develops in adults may have been put in motion before a person is born,” says the first author, Jennifer Cook, a graduate student who works with Walker at M. D. Anderson’s Science Park Research Division in Smithville, Texas.

The study was designed to challenge the longstanding notion that cancer arises when susceptible individuals are exposed to cancer-triggering compounds or events over the span of their lifetime. To test whether estrogen, found in both the environment and in some drugs, could reprogram tissue early, Walker, Cook and their team designed a study using female rats that are genetically predisposed to development of uterine leiomyoma, the same kind of benign fibroid tumors that many women have. Typically, 65 percent of rats carrying this genetic defect develop the tumors as an adult, and a set of these animals were used as a “control” group.

For the experimental group, researchers used another set of genetically susceptible rats and exposed them to DES, which is highly estrogenic, 3-5 days after they were born – a crucial period in the development of their reproductive tract.

They found that by the time they reached adulthood (16 months), virtually all of the rats in the experimental group had developed leiomyoma, and the tumors were larger and more numerous than in the control group. In contrast, none of the DES-exposed rats that lacked the genetic defect developed tumors by 16 months.

“The DNA of DES-exposed animals had been modified by DES in a way that changed how genes responded to estrogen, causing this tissue to be hypersensitive to the effects of this hormone,” Walker says.

The researchers theorize that DES had permanently altered the rat’s normal response to estrogen, a “reprogramming” of the normal physiological responses to estrogen, which led to cancer when the animal had an inherited genetic defect. In that way, DES had changed the “penetrance,” or likelihood of causing cancer, of the faulty tumor suppressor gene.