Could a combination of broccoli sprouts and green tea offer protection against breast cancer — and transform hard-to-treat breast tumors into a type that responds to medication?
A series of studies in the lab of UAB biologist Trygve Tollefsbol, Ph.D., D.O., have generated encouraging findings. Tollefsbol, who is also a senior scientist in the UAB Comprehensive Cancer Center, has shown that mice given sprouts in their chow and green tea polyphenols in their water are protected against tumor development. Intriguingly, he has also shown in animal studies that the combination can change estrogen receptor-negative (ER-) tumors, which have few treatment options, into estrogen receptor-positive (ER+) tumors, which can be treated with the anti-estrogen drug tamoxifen.
Now, Tollefsbol has received a $1.5-million, five-year grant from the National Institutes of Health to pinpoint the molecular mechanisms behind these effects. "We already have a lot of preliminary data showing that this combination works," Tollefsbol says. "The grant will allow us to extend that research and explore the effects genome-wide."
Tollefsbol's group hypothesizes that much of the cancer-fighting power of broccoli and green tea comes from epigenetic effects. Epigenetics focuses on the chemical markers surrounding genes, rather than the genes themselves. Because these markers affect the likelihood of a gene getting turned on or off, they play a crucial role in health and disease. (For a quick overview of epigenetics, see this infographic.)
Cigarette smoke and the sun's UV rays, among other things, alter epigenetic markers in harmful ways. Studies in Tollefsbol's lab and elsewhere suggest that compounds in certain foods have positive epigenetic effects. (In fact, Tollefsbol made headlines in 2011 with a paper explaining the health effects of what he calls the "epigenetics diet.")
Two compounds that appear to be particularly effective against cancer are sulforaphane (found in vegetables such as broccoli, kale, and cabbage) and green tea polyphenols (found in green tea). Each works through a different epigenetic mechanism, Tollefsbol explains. Sulforaphane inhibits histone deacetylases; green tea polyphenols inhibit DNA methyltransferases. But these two mechanisms "often work together to control genes," Tollefsbol says.
|UAB's Trygve Tollefsbol is exploring the hypothesis that broccoli and green tea help fight cancer by |
working through different epigenetic mechanisms to inhibit cancer-causing genes and boost tumor-suppressor genes.
That could explain why Tollefsbol's research has found that the combination of broccoli sprouts and green tea produces better effects than either compound alone. "The major problem with single agents is you have to consume too much," he says. Few people would be willing to drink a gallon of green tea every day, for example, and there is a limit to how much the body can absorb, anyway. "The idea is we need to find out what are the best combinations that will confer maximum protection."
In the current study, the researchers will use green tea polyphenols at the equivalent of about 2-3 cups per day of green tea consumed by humans and broccoli sprouts at the equivalent of about 1 cup per day in humans.
In order to analyze the cross-talk between different types of epigenetic changes, the UAB investigators had to invent a new technique. Chromatin immunoprecipitation-genomic bisulfite sequencing, which combines two individual tests, was developed in Tollefsbol's lab by Yuanyuan Li, Ph.D., currently an instructor in UAB's Division of Hematology and Oncology.
|In the current study, the researchers will use green tea polyphenols at the equivalent of about 2-3 cups per day of green tea consumed by humans and broccoli sprouts at the equivalent of about 1 cup per day in humans.|
This novel technique will allow the scientists to examine how their dietary combination affects tumor suppressor genes such as p16, for example, or the enzyme telomerase, which cancer cells need to keep up their endless cell division. (Learn more about how telomerase fuels cancer, and fights aging, in this related article.)
"It is also important for us to understand the global profile of the epigenetic effects of these compounds, and what other genes they may be impacting," Tollefsbol says. To do that, his lab is collaborating with UAB's Heflin Center for Genomic Science to analyze changes in DNA methylation and histone modifications across the genome in response to green tea polyphenols and broccoli sprouts.
From ER- to ER+
Tollefsbol is particularly excited to follow up on a surprising finding his lab made a few years ago. The broccoli-green tea combination, they found, can transform ER- tumors to ER+ tumors in mouse models. "We were very happy to see that," Tollefsbol says, "because estrogen receptor-negative tumors are a major problem."
Tollefsbol's group has since shown that sulforaphane, combined with a compound in green tea called epigallocatechin-3-gallate, "leads to reactivation of the estrogen receptor alpha gene" in ER- tumor cells, which allows them to be targeted by tamoxifen.
With the NIH grant, Tollefsbol will expand that discovery by looking at the combination's effects in two major subtypes of ER- tumors: SV40 and HER2/neu. "We think this has a tremendous amount of potential," Tollefsbol says. "These observations may lead to novel chemoprevention approaches for women at high risk of developing ER- breast cancer who have few other options."
Tollefsbol's team also hopes to find epigenetic biomarkers of ER- breast cancer. "There's a lot of interest in this area," he says. "At that point, you could predict if a person is predisposed to cancer. You could also use that information to monitor treatment as well. A doctor could look at epigenetic changes in the genome to see if they are normalizing in response to the drugs."
Get a quick overview of epigenetics in this video from UAB Magazine.