OF MICE AND WOMEN
Breast cancer researchers from around the world
gather in Sacramento to discuss the mouse
The OncoMouse has proved a valuable model of human breast cancer.
Women owe mice a debt of gratitude. Thanks to these oft-maligned creatures, doctors today have
a storehouse of knowledge about where early breast cancer starts and how the disease progresses. And now,
due to recent advances in genetic engineering and genomics, the lowly rodent is poised to make even greater
contributions. An international scientific conference devoted to just this topic employing mice
to end the suffering caused by breast cancer brings hundreds of researchers, biotechnology industry
representatives and breast cancer activists to Sacramento in November. Hosted by UC
Davis Cancer Center in conjunction with the National Cancer Institute's Mouse Models of Human Cancers
Consortium, the conference is only the second public scientific meeting to focus on mouse models of human
breast cancer in preclinical trials the studies that determine whether a new treatment prevents
or cures cancer before it is tested in women. Organizers hope to persuade more breast cancer investigators
to employ mice in their research, to clear up intellectual property rights obstacles, and to boost cooperation
between the biotech industry and nonprofit research communities.
"Our understanding of these mouse models has reached the point that they should be rapidly deployed
to help alleviate human suffering," argues Robert D. Cardiff, professor of pathology at UC
Davis School of Medicine and Medical
Center and director of the November meeting. "These marvelous animals need to be used."
The 24th Congress of the International Association for Breast Cancer Research meets at the Sacramento
Convention Center Nov. 1 through Nov. 5.
The meeting brings together more than 70 speakers from a dozen nations on four continents to report on
the latest developments from the laboratory, regulatory and business arenas. Nancy Brinker, founder of
the Susan G. Komen Foundation for Breast Cancer Research and the former U.S. ambassador to Hungary, delivers
the keynote address.
A brief history of mice
Use of the mouse in breast cancer research began in California 50 years ago, when Kenneth B. DeOme, professor
of zoology at UC Berkeley, established the Cancer Research Genetics Laboratory. Funded by the state, the
Berkeley-based lab maintained a colony of genetically similar mice to share with cancer researchers throughout
the world. From the 1950s through the 1970s, scientists at the lab established essential guidelines for
comparing mouse and human mammary lesions. These early investigators, Cardiff prominent among them, showed
that breast cancer in mice is uncannily similar to breast cancer in humans. The similarities allow scientists
to ask questions in mice that yield answers for women.
Breast cancer tissue in mice yields clues that help women.
The Berkeley group found, for example, that most breast cancers in mice start in the innermost milk ducts
and milk glands. UC Davis researchers Sefton
R. Wellings and Hanne M. Jensen then showed the same is true in human breast cancer, toppling the common
wisdom: Doctors had assumed most human breast cancers arose in the larger ducts closer to the skin's surface.
Without clues from the mouse model, the discovery could have been delayed for years. Cardiff and his colleagues
have now shown that in mice, ductal carcinoma in situ, a very early, localized form of breast cancer,
nearly always progresses to invasive disease. The finding provided laboratory evidence to support routine
surgery to remove DCIS lesions in human patients.
Cardiff and four Berkeley colleagues later joined the faculty at UC
Davis, where they began to build what has become the premier mouse biology program in the country.
Among its other claims to fame, the program is home to the Mutant Mouse Regional Resource Center, the
world's largest archive of mutant mice.
GEMs prove a treasure
The 1980s ushered in the era of the genetically engineered mouse. Called GEMs by their creators, these
rodents are custom-made to carry selected human genes. "The similarities between diseases of humans
and animals described by previous generations of scientists were frequently obscured by the difference
between the species," Cardiff says. "With GEM, the similarities have been emphatically confirmed
at the genetic and molecular level. The molecules that cause diseases in humans cause the same diseases
Once the stuff of science fiction, GEMs are now used to study cancer and other human diseases in labs
worldwide. Cardiff says 40 million transgenic mice are used each year for all research purposes combined.
Demand for the designer rodents is expected to nearly double every year.
Researchers create the animals by injecting a selected human gene into an egg from a female mouse right
after conception. Three weeks later, a cancer-prone mouse is born. Crossbreeding GEMs produces a long
line of mice with the defective gene.
Cardiff today keeps track of more than 6,000 GEM phenotypes in the Mutant Mouse Regional Resource Center
archive; more than 100 are mouse models of human breast cancer.
But in 1988 the world's attention focused on just one: the OncoMouse, engineered to carry a human gene
that all but destines it to develop cancer. The OncoMouse made history as the first animal to receive
The patent has generated controversy ever since. Harvard was awarded intellectual property rights not
just for the original OncoMouse, but for any mammal genetically altered to express oncogenes, the genes
that cause cancer. Harvard licensed the OncoMouse to DuPont, in an agreement that gives DuPont commercial
rights. Early on, DuPont argued that these rights included so-called "reach-through" rights,
requiring anyone who develops a product through use of a cancer-prone transgenic animal to pay royalties
to the company.
Over the last decade, some researchers who work with the OncoMouse have complained of barriers to using the animal, from limitations on sharing mice with colleagues to red tape in submitting scientific articles based on OncoMouse research. The National Institutes of Health weighed in earlier this year. "... Unnecessary delay of publication or prolonged exclusive use of the mice are not in the best interests of the research community or the public health," the agency said in a statement.
Cardiff argues now is the time to solve intellectual property rights issues, in order to increase use of the mouse in breast cancer research. Representatives from DuPont, an attorney from the National Cancer Institute and officials from the Food and Drug Administration all are invited to the meeting in Sacramento. On the agenda are opportunities for the parties to discuss new approaches to intellectual property rights, and new drug development regulations that would allow use of GEMs in investigational drug testing. Using mice in the earliest phases of new drug testing could reduce risks to human volunteers, and speed the drug-development process.
"Perhaps recognition by all interested parties that some sort of compromise is required will advance the use of GEMs in preclinical research," Cardiff says.
But the major focus of the 24th Congress is on research. Lewis Chodash, a cancer researcher at the University of Pennsylvania, presents the first mouse engineered to develop inducible cancer. The oncogene in this novel GEM is silent until the mouse is exposed to a certain drug, allowing scientists to control precisely when the lab animal will begin to develop cancer. "We've gained temporal control of the gene," says Cardiff, a co-investigator.
Sandy Borowsky and Jeff Gregg, cancer researchers at UC
Davis, report on their efforts to isolate DCIS genes in mice, and to identify parallel genes in humans.
"They've found a considerable number of mouse genes, and a considerable number of human matches,"
Cardiff says. "This opens the potential for interventions. If you know what genes are encoded early,
you may be able to block progression early. It's an exciting concept."
Simon Cherry, a bioengineer at UC Davis, reports
on a microPET (positron emission tomography) scanner small enough to image mice. Other presentations deal
with successful experiences using GEMs to test investigational cancer drugs, and the latest in stem cells
and antibodies in mouse models of human breast cancer.
"In breast cancer research," Cardiff says, "the genetically engineered mouse leads the way."