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 susceptibility
Keck 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 Medicine
Genetic 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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