Full Court Press
Pathologist Michael Press is involved in an unrelenting scientific pursuit of the genetic links to women's cancers.
Michael Press, M.D., Ph.D., is on the phone, his voice calm and reassuring.
He is talking to a physician whose patient, a woman with an aggressive case
of breast cancer, is hoping to qualify for a clinical trial of a drug that
seems to work best in women who have a specific gene mutation. Press, a professor
of pathology at the Keck School of Medicine of USC and coordinator of the
USC/Norris Comprehensive Cancer Center's breast cancer research program, is
acting as a sort of gatekeeper for the trial, analyzing cell sample after
cell sample to ensure that only those women with the cell types most likely
to respond to the drug in question
are admitted.
After assuring the physician that the results of the cell sample analysis should be available soon, Press hangs up the phone with a slight grimace. "It's hard," he admits. "There's so much at stake."
Press knows that the results of this trial may be critical in determining
the future treatment of thousands of women with breast cancer. But he also
knows that the results of this single cell typing are equally critical to
the woman whose physician just called. It is difficult to balance these often-competing
interests, but Press, a scientist with a physician's gift for compassion and
empathy, does it almost effortlessly.
And it shows. In 1998, Press was awarded the Harold E. Lee Chair in Cancer
Research, part of a $5 million gift from philanthropist Henrietta C. Lee in
honor of her late husband. Peter Jones, Sc.D., director of the USC/Norris
Cancer Center, calls Press "the Norris' leading basic scientist in the
study of the molecular and genetic causes of breast and ovarian cancer."
In October of this year, the Breast Cancer Research Foundation-which supports
some of his ongoing clinical research-honored him at its Seventh Annual Symposium
and Awards Luncheon.
"I've always been fascinated with trying to understand why one person
becomes ill and another doesn't, or why one person's disease progresses and
another's doesn't," he says. "That's what led me to pathology."
Gone fishing
And pathology has led him to the scientific pursuit of a number of genetic
links to women's cancers. One of the longest of these quests has centered
on a gene for a protein called HER2/neu.
The HER2/neu protein is a cell-surface receptor that plays a role in sending
growth signals to the cell's nucleus. When this gene is overexpressed-prompting
the production of several times the normal number of receptors-the cells carrying
that gene tend to grow faster than usual. As it turns out, HER2/neu is overexpressed
in 25 to 30 percent of human breast cancers, making them unusually aggressive
and more likely to metastasize and recur.
Press is involved in HER2/neu research in a number of different ways. For
one, there is that clinical trial the concerned doctor was calling about-a
trial under the auspices of the Breast Cancer International Research Group
(BCIRG) that hopes to determine whether the drug herceptin-a monoclonal antibody
that grabs onto the HER2/neu protein receptor and prevents its signal from
being sent-is truly the best way to treat newly-diagnosed breast cancers that
overexpress the gene. Press' lab is the international testing site for that
trial-the laboratory through which samples from all over the world are routed,
and where it is determined whether the breast cells in those samples actually
overexpress HER2/neu. To date, says Press, they have screened more than 2,000
patients' cancers.
"We're excited about being part of this trial," he says. "I
really think it will improve our approach to breast cancer therapy."
The Press laboratory was chosen as the testing site for the trial because
Press and his colleagues were recently involved in getting one of the most
accurate methods to characterize these sorts of cell-surface receptors that
has been approved by the Food and Drug Administration-a process called fluorescence
in-situ hybridization, or FISH. "Although most places don't use FISH
as yet," says Press, "when it comes to gene amplification and overexpression,
this is the way to go." Clearly, the BCIRG agrees.
So do a number of other researchers, both within the Keck School and outside.
For instance, Press is currently collaborating with Leslie Bernstein, Ph.D.,
the AFLAC Chair in Cancer Research and professor of preventive medicine at
the Keck School, in a study of about 1,500 women with invasive breast cancer
as part of the large-scale Women's Contraceptive and Reproductive Experiences
Study (CARE). Together, they are examining a number of different genes and
hormones that might play a role in making one individual's cancer more belligerent
than another's. And, along with Shelley Enger, an epidemiologist from Kaiser
Permanente, Press is working to characterize breast cancer's cellular and
genetic alterations, and determine whether those changes can be linked to
either positive or negative responses to various chemotherapy drugs.
"We're looking to see if we can show a correlation between genetic alterations
and a patient's potential for responding to the different forms of therapy,"
says Press. "I've been involved in this for quite a while."
Cell behavior
Press is equally involved in pursuing basic scientific questions-what he calls
"the really exciting stuff"-such as determining precisely why an
overexpressed HER2/neu gene makes tumor cells so aggressive and dangerous.
To do that, Press has engineered HER2/neu overexpressing cells in laboratory
dishes, and is finding that overexpression of the gene has an impact on some
of the cell's most basic processes, like the ways in which cells adhere to
various tissues in the body.
"Cells that overexpress HER2/neu actually adhere less tightly to the
tissues," he says. "Which makes sense if you realize that in order
to metastasize, a cell needs to be able to move more easily. HER2/neu seems
to permit the cell to do this."
Press has also found that a revved-up version of HER2/neu can make it easier
for cancer cells to migrate from place to place and to invade new tissues.
And from preliminary studies, he says, it looks as if too much HER2/neu also
decreases apoptosis-the cellular version of suicide.
"The goal is to try to understand what HER2/neu does to cells to change
those behaviors," Press says. "Then, once we know the steps, we
can see if we can intervene-and where."
Inherited cancer
The story of breast cancer, and of Press' pursuit of a cure, neither begins
nor ends with HER2/neu. When Press was at the University of Chicago-where
he received a Ph.D. in cell biology in 1975 and an M.D. in 1977-he actually
entered the breast cancer arena studying the estrogen receptors in the nucleus
of women's cells. "We would look at estrogen receptors in the clinical
setting to determine who to treat with hormones-and who not," he explains.
(Breast cancer cells that sport these receptors are more likely to proliferate
out of control in response to female hormones; cancers without the receptors
can be more safely treated with hormones.)
In the mid- to late-1980s, Press became intrigued by work in the laboratory
of Dennis Slamon, M.D., Ph.D., at the University of California, Los Angeles.
Slamon was one of the first researchers in the country to study HER2/neu,
and Press wanted to be part of that groundbreaking work. So, in 1987, he took
a sabbatical from his position as associate professor at the University of
Chicago, and headed to Los Angeles; when the sabbatical was over, he accepted
a job offer at USC. "I really liked the department here," he says
simply.
Once ensconced at the USC/Norris Cancer Center, Press resurrected his interest
in estrogen receptors and breast cancer. Quickly, he began to realize that
estrogen alone is only part of the equation. "The estrogen receptor's
function is to recognize the presence of the hormone and cause other genes
to be turned on in the cell," he says. "But they don't do it alone.
They require co-activators-other enzymes and proteins that make the expression
of the estrogen receptor much stronger." To pursue this area, Press collaborated
with Michael Stallcup, Ph.D., Keck School professor of pathology and a leading
scientist in the study of steroid hormone receptor co-activators.
Among those co-activators is one of the genes that is considered responsible
for the inherited forms of breast cancer-BRCA1. Mutated BRCA1 is linked to
about 10 percent of breast cancers; women with the mutated gene have an extremely
high risk of developing breast cancer relative to women who lack the mutation.
But Press believes that is not the entire story of BRCA1 and breast cancer.
"We assume that it not only has a role in hereditary cancers, but also
a role in breast cancers that are not hereditary," he says.
That is why Press' laboratory is looking into the role of "wild type"
BRCA1-the non-mutated version of the gene. And what they have found is that
women with non-hereditary breast cancers tend to have a reduced or a complete
loss of expression of the BRCA1 gene. In other words, the
non-mutated BRCA1 seems to play a role in controlling the expression of growth
signals in cells. When paired with estrogen and other hormone receptors, says
Press, wild type BRCA1 may play a more critical role in spontaneous breast
cancers than it does in its mutated form in inherited breast cancer. And that,
he adds, may lead to new therapeutic options for women with the disease.
That sort of thinking is typical of Press. When he investigates a potential
breast cancer culprit-HER2/neu, estrogen receptor status, the BRCA1 gene or
other proteins and genes that are postulated to play a role in the disease-he
never forgets that his job is to help bring findings from the laboratory to
a patient's bedside. "We're very interested in translational medicine
at the Norris," notes Press. "It's the logical next step when you're
doing any phase of cancer research."
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