Spotlight on

Grace C. Yeh, Ph.D.
Chief, Cellular Defense and Carcinogenesis Section
Center for Cancer Research, NCI

Spotlight Archive

Growing up in Taiwan, Dr. Grace Yeh never thought of science as a possible career choice. Like many other little girls at that time, she was planning to be a teacher when she grew up. And, who knows, if Dr. Yeh had grown up in a different family she might just be teaching now instead of directing research into the mechanisms of cancer prevention. It just so happens her father, a physician, had a strong influence on Dr. Yeh as she was growing up. He exposed her to science and the wonders of biology.

As an undergraduate, Dr. Yeh took a wide range of math and science courses, but she was really drawn to biology. "I liked biology, it was something I could relate to," she recalls. Although she did well in physics and organic chemistry, these subjects were just too abstract to keep Dr. Yeh's interest. "Calculus was my worst subject--it was just a lot of equations and I did not enjoy this at all," she adds. Dr. Yeh enjoyed her courses in cell biology, physiology, and biochemistry. She liked the "hands on science" that happens in the laboratory and found that she was quite good at it. This made Dr. Yeh a somewhat "puzzling" student in the eyes of her teachers. "The philosophy of learning [in Taiwan] is somewhat different than it is here [in the U.S.] because in Taiwan memorization is the basic thing," she explains. "You have to memorize all the equations, the pathways, and so on." In the lab Dr. Yeh found that she could be more creative. "You can really develop your thinking while working in the laboratory," she says. "So, even while I was growing up I was somewhat different because my teachers just didn't understand why I was an A, B, C student in my textbook work but was always a 'straight A' student in my lab work. I think I just liked the challenge of doing things--coming up with a concept and then developing that concept into something real." The positive lab experience that Dr. Yeh gained as an undergrad gave her the confidence to go on to graduate school at the University of Massachusetts, where she earned her master's degree, and then to the University of Maryland, where she earned her PhD.

Dr. Yeh's graduate and post-doctoral experiences allowed her to work with many different scientists and she feels that this was an important part of her professional growth. "I really cannot name just one person who influenced me," she says. "I have been very lucky because all the scientists that have worked with me--even back in graduate school--have shared their ideas and thoughts; we influenced each other." "Even now, in my own section, my colleagues continue to influence me and I advise them--it is a two-way street," she explains. "That is why I enjoy doing research, it is a constant learning process . . . I just know a certain area, that's all." Dr. Yeh emphasizes that although she is a mentor, she is always learning something new from her postdocs and co-workers.

Chemotherapy versus Multi-Drug Resistance
During graduate school, while she was majoring in nutritional science and biochemistry, Dr. Yeh started thinking about how she could apply her education to the 'fight against cancer'. After receiving her PhD, Dr. Yeh was hired by NCI's Metabolism Branch and gained valuable experience working with physicians in this branch. Her first project involved basic research on intermediary metabolism in the proline cycle. In 1982 she joined the Medicine Branch, working under Dr. Bruce Chabner as a Cancer Expert. Dr. Yeh became a Principal Investigator in 1984, with a joint appointment as Assistant Professor in the Department of Pharmacology at the U.S. Uniformed Services University of Health and Science (USUHS). She was promoted to Associate Professor at USUHS in 1990. During this time, her studies involved chemotherapeutic research focusing first on anti-metabolite activation and then on multi-drug resistance (MDR) biochemical regulation in breast cancer tissue culture cells. MDR is, in essence, a survival mechanism that tumor cells use to "outsmart" the chemotherapeutic drugs that are trying to "kill" them. And, many of the drugs used to fight cancer are toxic--these drugs can kill and damage many normal cells while attacking the cancer cells. At this point, Dr. Yeh became interested in finding out whether there was something that could be done to prevent cancer using natural products, rather than treat cancer after it has developed.

Dr. Yeh was recruited by Dr. Peter Greenwald the Director of the Division of Cancer Prevention and Dr. James Phang (Laboratory Chief) to set up a lab focusing on cancer prevention at NCI-Frederick. "I was really excited, so I dropped everything to move up here to Frederick, where I have been working for the last 12 years," she recalls. One of Dr. Yeh's first projects in Frederick focused again on MDR and how it helps tumor cells survive chemotherapy. During MDR tumor cells react to the onslaught of chemotherapeutic drugs by developing a P-glycoprotein (P-gp) drug efflux pump. This pump 'effluxes out' the chemotherapeutic drugs that allow the tumor cells to survive. Most chemotherapy is given in several cycles, usually 6. In the first 2-3 cycles, the patient responds because the tumor cells are being killed and the tumor shrinks or stops growing. During the later cycles the patient stops responding to the chemotherapy because the tumor cells have developed MDR, due to this P-gp drug efflux pump. "At this time, when I was working with MDR, we tried to block this pump for the benefit of cancer patients," Dr. Yeh explains. "We were studying the mechanism of this pump and trying to 'block it' using natural products, but it was kind of unsuccessful. During this process however, I did find out that, in our normal human tissues, we all have this P-gp mechanism. And I was wondering what could the P-gp do in normal tissue? Could it efflux out carcinogens? Most cancer development is due to environmental carcinogens. And, most carcinogens do not become toxic until they are activated. For example, arylhydrocarbons are not toxic until they become activated. If the P-glycoproteins could efflux carcinogens out of normal tissues, then carcinogenesis could never be initiated."

Chemoprevention: Getting Rid of Carcinogens
The concept of using the P-gp efflux mechanism to help prevent rather than promote carcinogenesis, was the starting point for Dr. Yeh's first research study focusing on chemoprevention. "We were trying to understand whether the phytochemicals found in fruits and vegetables could enhance this efflux mechanism, and if this mechanism could indeed efflux out carcinogens," she notes. Many U.S. epidemiological studies had already demonstrated that people who eat more than 3 servings of fruits and/or vegetables per day had lower rates of cancer. A World Health Organization study found that Asians had lower rates of breast and prostate cancer (both are hormone-regulated) because Asians do consume more fruits and vegetables, particularly soybeans. This led scientists to think there were certain components in soy protein that produced a chemoprevention effect, and all these studies formed the basis of the NCI's recommended 5-a-day program, "Strive for Five." Although many studies had confirmed the importance of fruits and vegetables in preventing cancer, the biochemical mechanism(s) that actually drive this chemoprevention are unclear.

Dr. Yeh's laboratory was the first to discover that a new functional role for the P-gp efflux pump is to serve as a carcinogen efflux mechanism (Cancer Res 52: 6692-5, 1992). They also identified several phytochemicals that help enhance this carcinogen efflux mechanism (Cancer Res 53: 5977-81, 1993). Dr. Yeh was honored in 1995 with the NIH Award of Merit for "establishing a research program investigating the P-glycoprotein and multi-drug resistance in cancer prevention." "From this point on, we focused on the activation step of arylhydrocarbon metabolism," Dr. Yeh explains. Arylhydrocarbons are common environmental carcinogens such as benzopyrene, which is found in the air we breathe from carbon combustion, cigarette smoke, and charcoal grilled food. Benzopyrene and other arylhydrocarbons are activated to genotoxic metabolites by a biochemical pathway that is regulated by the arylhydrocarbon receptor. "We all have lots of arylhydrocarbon receptors in our bodies, but these receptors are not active" says Dr. Yeh. "Only when this receptor binds to an arylhydrocarbon is this pathway activated, resulting in activation of the arylhydrocarbon and, ultimately, carcinogenesis," she adds. Dr. Yeh's lab is currently trying to find out which phytochemicals can interrupt the different stages of carcinogenesis. "We have discovered several phytochemicals that can inhibit this initiation process and block the binding of the arylhydrocarbon to its receptor," says Grace. Her lab has already demonstrated this chemopreventive effect in tissue culture such as human breast, colon, and hepatic cells and they are now trying to develop an animal model for lung cancer. They plan to use phytochemicals in the diet to attempt to prevent the development of lung cancer tumors in mice.

Fruits, Vegetables, and Red Wine?
So, we all know that we need to eat more fruits and veggies, but is there any one fruit/vegetable that stands out in terms of its chemopreventive effect? "The thing is, there is no one fruit or vegetable that is so special compared to others," says Dr. Yeh. "All fruits and vegetables have different phytochemicals, and there are at least 1,000 different kinds of phytochemicals: isoflavones, flavenoids, catechines, etc. Some of the more well-studied phytochemicals include certain catechines found in green tea; these catechines have been found to prevent lung and skin cancer in animal models. Soy protein products, especially genistin, may also be relevant," she adds. Initially, researchers were interested in many of the phytochemicals because a number of these chemicals act as anti-oxidants. The formation of reactive free radicals during carcinogen metabolism can result in DNA mutation. Anti-oxidants, on the other hand, detoxify carcinogen-induced reactive free radical formation. Certain anti-oxidants also enhance the mechanism of the phase-II enzyme system; these enzymes can detoxify and/or conjugate carcinogens to be more water soluble, helping you excrete these toxins from your body.

Resveratrol, a phytochemical found in red wine, has also been proven to be a powerful anti-oxidant. Because red wine, unlike white, is made using the whole grape, including the skin, the resveratrol becomes highly concentrated during the fermenting process. "People are always asking me, 'How many glasses of red wine do I need to drink to get the beneficial effect?'" Dr. Yeh said. "The thing is, you don't need to drink a lot, only a glass a day, and only if you enjoy it," she adds. "There are other sources--all fruits and vegetables have anti-oxidants. For example, oranges and other citrus fruits all contain phytochemicals that enhance phase-II enzyme production and act as anti-oxidants. Green leafy vegetables are also very good anti-oxidants and act similarly, although the biochemical pathways that they affect are somewhat different," she explains.

In her own life, Grace has always lived by the 5-a-day rule, although she does like a good charcoal-grilled steak now and then. "I do, however, have a glass of red wine to counteract the effects of the benzopyrene that I have just eaten," she adds. Dr. Yeh believes that there is no "magic bullet" out there that anyone can take to help prevent cancer and that moderation and balance are the keys to a healthy diet. "I eat in moderation and I don't deprive myself of anything that I enjoy," she adds. All phytochemicals can prevent cancer and the more different kinds of fruits and veggies you can consume the better.

Dr. Yeh believes that within 5-10 years we will have a much better understanding of the molecular targets and biochemical pathways that are relevant to carcinogenesis and how they are affected by phytochemicals. She would like to start a Natural Product Working Group to enhance our understanding of these natural chemicals and how we can use them to prevent cancer. Dr. Yeh hopes that we can one day make certain phytochemicals or synthetic derivatives that people could take once-a-day, as they do vitamins, to help prevent cancer. She does not advocate the use of nutritional supplements, which are widely available, because the Food and Drug Administration does not regulate these substances; this lack of regulation means there are no recommended safe dosages for any of these products. If you take too much of any one of these powerful chemicals, you could be doing yourself more harm than good. "When you give any purified compound [including natural products] in a mega-dose, it is a drug, so the general public needs to be aware of this," Dr. Yeh cautions.

The NCI Community: Giving Something Back
In addition to all her research activities, Dr. Yeh is very active in service to the wider NCI community. She has always been interested in mentoring young scientists, and, in 2001, Dr. Yeh won the NCI Mentor of Merit Award. She has also served three terms as an advisor to women scientists and she is a founding member of the Women's Scientist Advisory Board of NCI. The NCI Advisory Board is part of a larger NIH-wide organization initiated by former NIH Director, Dr. Bernadine Healy. Dr. Healy saw a need to help close the gender gap that is evident throughout the NIH. At the postdoc level, there is no discernible gender difference; however, at higher-level positions, a PI or higher, there is a big gender difference. "Right now, at the PI level, including tenured and tenure-track, it is about 85% male and about 15% female," explains Dr. Yeh. "What is happening--Why do the females not make it, why do the males make it? We want to know where the problem is; you have to know the problem in order to address it," she adds. This group advises the CCR Director on a variety of topics of particular interest to women scientists, and has been instrumental in developing a number of initiatives that have affected the professional lives of women scientists at NCI. "I am really very proud to say that NCI, for the last 5 years, has made the most progress [within the NIH] in trying to solve these problems for women scientists," says Dr. Yeh. The Women's Scientist Advisory Board works closely with the NCI Fellowship Office on recruitment issues and has established several awards specifically for women scientists. Dr. Yeh has also helped establish meetings and workshops devoted to assisting women scientists in communicating and negotiating with their supervisors on issues such as salary, lab space, and support. "I hope our workshops have helped in making women scientists at the NCI a bit more assertive," she says. So, does Dr. Yeh think there is a "glass ceiling" at NIH? "No, I don't think so," says Dr. Yeh. In fact, she thinks that some women may make a choice to be an administrator rather than a scientist because they have children to care for or some other personal reason.

Dr. Yeh is also contributing her time to several intramural faculties. She currently serves on the Cellular, Molecular, and Developmental Biology Faculty's Communication Committee and helped organize the 2003 Molecular Carcinogenesis Workshop. During 2003 Dr. Yeh has also served on the Hormones and Cancer Retreat Steering Committee and the Cancer Prevention Faculty Steering Committee.

More interesting research into the mechanisms of cancer prevention as well as more mentoring, advising, and service to the wider NCI/NIH community is what the future holds for Dr. Yeh. As for Dr. Yeh's successful career as a cancer researcher, we have to give credit both to Grace and to her father. It is truly amazing how much influence a father can have on his daughter.

Written by Susan Fox
Office of Communication
Center for Cancer Research (CCR)
National Cancer Institute at Frederick

Edited by:
Kathryn Ellis, Office of Communication, CCR
Maritta Grau, Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.

Photography by Martha Welch
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.

Web Graphics and Development by Jim Miller
Computer & Statistical Services
National Cancer Institute at Frederick