Roots of Risk
A complex web of variations among ethnic groups may determine an individual woman's breast cancer fate.
What do an African-American music executive from Los Angeles, a Southwest rancher's wife of Mexican descent and a Japanese-American mother of three have in common?
They all may be sisters in the fight against breast cancer.
Researchers at the Keck School of Medicine of USC are studying breast cancer in diverse ethnic groups to better understand which women are especially at risk for the disease and why. By exploring reasons why the malignancy is more common among certain ethnicities, scientists hope to learn more universal lessons about the underlying causes of breast cancer among individual women across the globe.
By analyzing breast cancer rates in large populations, researchers can identify whether women are at greater or lesser risk for breast cancer according to ethnicity or race. They identify lifestyle factors specific to those populations, such as diet, that might influence the chances of getting cancer. Finally, they zoom in on parts of the DNA code linked to risk.
The more they uncover, the more researchers believe that breast cancer results from an interplay between environmental factors-those coming from outside the body-and genetic factors originating within it.
Asian experience
When it comes to the risk of getting breast cancer, statistics show the disease
discriminates. Non-Hispanic white women have the highest risk of breast cancer, followed in order by African Americans, Asians and Pacific Islanders, Hispanics and American Indian and Alaskan natives, according to 1999 National Cancer Institute figures on cancer rates.
But the rates and risks are changing, and finding reasons for such changes might illuminate risk factors.
Asian-American women, for example, have traditionally had fewer cases of breast cancer than most other women, but their rates are growing. In Los Angeles County, breast cancer cases among Asian women 50 years or older increased more than 6 percent a year from 1993 to 1997, says Dennis Deapen, Dr.P.H., professor of preventive medicine at the Keck School of Medicine and director of the Los Angeles County Cancer Surveillance Program. Cases among non-Hispanic white women increased less than 2 percent a year during the same time. Breast cancer rates in Los Angeles are similar to rates nationwide.
When they divided Asian Americans up by national origin, researchers saw that Japanese-American women, in particular, face growing risk.
"If trends from the 1990s have continued, rates among Japanese-American women in Los Angeles County may have surpassed those of non-Hispanic white women, who have historically had the highest rates of breast cancer," Deapen says. "Breast cancer incidence for Japanese-American women in Los Angeles County is the highest reported for Japanese women living anywhere in the world."
In 1997, Japanese women experienced 114 cases of breast cancer per 100,000 women. Filipina women had about 98 cases per 100,000, Chinese women had about 51 per 100,000 and Korean women had about 45 per 100,000. Rates rose between 1993 and 1997 for all except Chinese women.Breast cancer risk increases follow a pattern of immigration to the U.S. and increasing westernization, Deapen says. Among the four Asian groups mentioned, Japanese were the first population to migrate to Los Angeles County in substantial numbers, followed by Filipinos. Chinese and Koreans tend to be less acculturated immigrant populations.
Anna Wu, Ph.D., professor of preventive medicine, has been tenaciously following the increases in cancer among Asians since the early 1990s.
That is when she and preventive medicine professors Brian E. Henderson, M.D., and Malcolm Pike, Ph.D., conducted one of the first studies on breast cancer among middle-aged Asian women. They found a shift toward higher risk linked to western trends: starting puberty early, having fewer children and postponing first live birth.
In the dietary part of that study, Wu asked women whether they ate tofu, almost as a throwaway question since tofu is a staple of the Asian diet. Surprisingly, she says, "We saw that Asian women who developed breast cancer had considerably lower tofu consumption than those Asian women without cancer."
Soy consumption among Asian women typically shrinks the longer they live in the United States, and at the same time, Asian women in the U.S. are eating more fat.
Fat typically accounts for 30 to 35 percent of total daily calories in the U.S.
Wu and colleagues are now studying more than 1,000 pre- and postmenopausal Chinese, Filipina and Japanese women in Los Angeles to better understand any link between traditional soy foods and low dietary fat and cancer protection. Researchers are investigating whether soy foods are protective or if they just
happen to be a surrogate for some other protective behavior.
Together with Mimi Yu, Ph.D., professor of preventive medicine, Wu recently found that postmenopausal women in Singapore who eat soy foods have lower
levels of estrone, a type of estrogen, circulating in the blood.
Evidence suggests that the more exposure to estrogen, the greater the breast cancer risk. The ovaries produce estrogen, which travels through the blood to the breast and other tissues. Estrogen stimulates breast cells to divide and multiply. The more breast cells multiply, the greater the chance that genetically faulty cells will arise. Cancer results when abnormal cells multiply out of control.
It is still too early to be sure the Asian diet helps reduce risk, but to Wu, growing rates of breast cancer among Asian Americans hint that lifestyle factors may be important for all women.
"The good news," says Deapen, "is that these factors can potentially be altered."
Hispanic susceptibilityKeck School researchers are among the few to look at breast cancer risk among Hispanic women, too.
Frank D. Gilliland, M.D., Ph.D., M.P.H., professor of preventive medicine, and colleagues conducting the New Mexico Women's Health Study found that weight gain and high body fat, family history of breast cancer, alcohol use and long-term use of hormone replacement therapy were linked to increased breast cancer risk in Hispanic women. Physical activity and breast-feeding reduced risk.
"We know that breast cancer incidence and mortality have been rising in Hispanic women, but no one knows why," Gilliland says. "The thought was that perhaps these women were starting to have fewer children, and having them later in life, which may increase risk.
"But we looked at all the major reproductive factors, and they explained only 5 percent of the increase in risk. Something else must be going on."
Researchers studied more than 1,500 women with breast cancer and found that breast cancer risk more than doubled for Hispanic women who had gained 30 pounds or more during adulthood. Among non-Hispanic white women who gained similar weight, only postmenopausal women faced increased risk.
Breast cancers associated with weight gain among Hispanic women and postmenopausal non-Hispanic white women were mostly estrogen- and progesterone-receptor positive (ER+/PR+). These tumors depend on estrogen and progesterone to grow.
Although researchers do not quite know how weight gain affects cancer risk, the association of ER+/PR+ tumors with weight gain points at hormones' importance.
"Aside from estrogen, other hormones like insulin and IGF-1, an insulin growth factor, may play a role in breast cancer," Gilliland says. Hispanics appear susceptible to obesity-about a quarter of Hispanic women are obese- and have a high prevalence of insulin resistance, leading to elevated risk for type 2 diabetes, so weight gain may play a big part in cancer risk in this group.
Gilliland and colleagues have found that physical activity outside of work, such
as walking or dancing, reduces breast cancer risk among both Hispanic and
non-Hispanic white women. Other studies indicate that high-energy leisure-time
exercise reduces breast cancer risk by about 30 percent.
Interestingly, physical activity seems to protect premenopausal Hispanic women more than their non-Hispanic white counterparts. Women who exercise a lot store less fat in their abdomen, which might reduce hormonal exposure. Some surmise that because Hispanic women are more likely to store fat around the abdomen, physical activity would be especially helpful in deterring breast cancer in those women.
African-American clues
Gilliland also is part of the Healthy Eating and Lifestyle (HEAL) study, along with colleagues in Washington state and New Mexico. In that still-ongoing study of diet, body weight, exercise and hormones, researchers are following several hundred African-American women.
Although breast cancer is less common in African-American women than white women, African-American women have a greater risk of dying of the disease. Some think lower availability or quality of health care may be to blame, or that tumors may be more aggressive in African-American women. But no one is certain.
"The issue of African-American women and breast cancer has been a difficult problem for people to tackle," says Leslie Bernstein, Ph.D., professor of preventive medicine and AFLAC Chair in Cancer Research, who conducts the HEAL study at USC with Gilliland. "For too long, information on African-American women's health has been missing because too few of them were included as participants."
Fortunately, African Americans made up more than a third of the participants
in the Women's Contraceptive and Reproductive Experiences Study (CARE). Bernstein, the principal investigator of CARE at USC, invited numerous researchers to expand on the study and use the findings to better understand cancer in women of various races.
Using data from this study, Bernstein and her collaborators showed that oral contraceptive pills, as currently formulated, do not affect the breast cancer risk of white or African American women. This study was published at the end of June in the New England Journal of MedicineGenetic culprit
Genetic answers to cancer mysteries lie within plastic plates punched with 384 tiny hollows, each holding a unique DNA sample. Every day, graduate students in a Keck School lab evaluate DNA from thousands of samples and gather information about the specific genetic codes that may protect or predispose people to cancer.
Each DNA sample originated from blood specimens donated by participants in the Hawaii/Los Angeles Multiethnic Cohort Study, a study comprising 215,000 people and funded by the National Institutes of Health and led by Henderson, the Kenneth T. Norris Jr. Chair in Cancer Prevention.
Nearly a decade after his study started with analyses of diet and other factors, Henderson has come to staunchly believe that genetics are the biggest determinant of risk for breast cancer.
"Work over the last 30 years indicates that the internal milieu-genetics-not the external milieu primarily affects breast cancer risk," Henderson says.
In addition to longtime collaborator Pike, faculty assisting in the study include: Ronald K. Ross, M.D., Flora L. Thornton Chair in Preventive Medicine; Gerhard Coetzee, Ph.D., associate professor of urology, molecular microbiology and immunology and preventive medicine; Juergen Reichardt, Ph.D., associate professor of microbiology and biochemistry; and Daniel Stram, Ph.D., associate professor of preventive medicine.
Scientists know that women with mutated versions of genes called BRCA1 and BRCA2 have as much as an 85 percent chance of developing breast or ovarian cancer during their lifetimes. But such mutations are rare. Henderson now seeks genetic variations that wield smaller risks for breast cancer but are far more commonplace.
Henderson's team is searching for a complex web of variations in genes that together comprise an individual's cancer fate. DNA sequencing and genotyping is done at the Whitehead/MIT Center for Genome Research in Massachusetts and at USC.
Postdoctoral fellow Chris Haiman, Sc.D., calls it "the colossal project." It is no wonder, with tens of thousands of genes to sift through.
Haiman explains that he and colleagues use haplotypes as a way of looking through the genetic code for important targets. A haplotype is a common grouping or pattern of alternative forms of a DNA sequence within a DNA chain, and it can occur in numerous different versions from person to person.
Because of the way humans developed and stayed within ethnic communities and geographic borders, members of an ethnic group or race tend to have some haplotypes in common. Chinese people might have one version, while those of northern European descent tend to have another, for example. Since whites have higher breast cancer rates, a researcher might seek a genetic culprit for cancer within a specific haplotype more commonly seen in whites.
First, researchers start with a DNA sequence that encodes a gene they know is involved in synthesizing hormones, such as progesterone, estrogen or IGF-1, and look for common haplotypes within it.
"The next step is to compare the frequencies of these haplotypes between
people diagnosed with cancer and those without cancer," Haiman says.
Risks associated with individual genetic variations are likely to be small-perhaps posing only a 40 percent increase in risk, he says. But this risk may be widespread across the population.
In the future, the information might be used to customize patients' cancer-prevention plans or develop targets for drug therapy.
Henderson, Haiman and other colleagues are looking at haplotypes associated with 25 genes, and expect to tackle another 20 genes in the coming years. New software from Keck School biostatistics faculty will speed the process dramatically.
Today, regardless of race, no one can trace cancer's exact roots in any individual. Henderson believes the keys to cancer, though, will be uncovered as scientists race to complete maps of the human genome and methodically link variations in genes to the roles they play in the cancer process.
"This is an unfolding story," Henderson says, "and it will continue to unfold over many years-beyond our lifetimes."
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