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A new $15.5 million, five-year grant from the National Cancer Institute was awarded this spring to the Institute for Cancer Genetics to study breast cancer. The researchers hope the grant will enable them to put together a coherent picture of the molecular pathways that lead to the development of breast cancer.

“Understanding the molecular details in the pathways should lead to more drugs like Herceptin, the only ‘rationally designed’ drug available for breast cancer today,” says Dr. Riccardo Dalla-Favera, director of the institute and the grant’s principal investigator.

The drug specifically targets cancer cells by attaching to Her2 receptors, which are present in 20 percent of human tumors. Once attached, Herceptin directs the immune system to kill the cells. Traditional chemotherapy drugs, which were identified after thousands were screened for their ability to kill cells, affect all rapidly dividing cells, not just malignant ones.

“With Herceptin, we’re now moving into the era of targeted therapeutics,” says Dr. Dalla-Favera, Percy & Joanne Uris Professor of Pathology and professor of genetics and development. “But it’s only effective in Her2-positive tumors, so we will need many such drugs that can attack different aspects of the tumor.”

The problem in designing new drugs is that scientists know little about the molecular changes that govern breast cancer. “So far, we know cancer starts with changes in genes, and in about 10 percent of breast cancer cases, the first genetic change is inherited,” Dr. Dalla-Favera says. “But in 90 percent of cases there’s no inherited disposition. In these cases we know a few genes, but we don’t know how the genes are linked and how the pathways are altered.”

The investigators participating in the newly funded grant already have an established track record in studies of genes implicated in breast cancer and should be well positioned to identify new factors responsible for this disease. In 1983 Dr. Dalla-Favera isolated the c-Myc gene, a proto-oncogene that is hyperactive in nearly two-thirds of patients with breast cancer. Dr. Richard Baer, professor of pathology at the institute, identified BARD1 in 1996 and showed that it is the essential partner of BRCA1, a tumor suppressor mutated in many cases of familial breast cancer.

The following year, Dr. Ramon Parsons, associate professor of pathology in the institute, discovered PTEN, another tumor suppressor implicated in breast cancer and other human malignancies. Dr. Argiris Efstratiadis, Higgins Professor of Genetics and Development, and Dr. Thomas Ludwig, assistant professor of anatomy and cell biology, have been among the first to exploit sophisticated mouse genetics to produce faithful animal models of human breast cancer. The newest member of the team, Dr. Wei Gu, assistant professor of pathology at the institute, has developed one of the world’s premier laboratories studying the p53 tumor suppressor, the most commonly mutated gene in human cancer.

In theory, unknown molecules that control these genes in breast cancer cells could be used to turn tumor suppressors back on or turn proto-oncogenes off. For example, Dr. Parsons will search for molecules upstream and downstream of PTEN that are necessary for tumor development. “Ultimately this research will find the best points of attack for potential therapies,” says Dr. Dalla-Favera.

Once identified, the newly discovered genes will be removed from, or overexpressed, in the breast tissue of mice to see if tumors develop, thereby testing their importance in breast cancer. This portion of the project relies on the expertise of Drs. Ludwig and Efstratiadis, who are both producing mouse models of breast cancer that will be analyzed in collaboration with Dr. Matthias Szabolcs, associate professor of clinical pathology. Dr. Efstratiadis has developed a new method for expressing cancer-inducing oncoproteins in specific tissues, including the breast, and Dr. Ludwig is generating mouse strains with targeted lesions in the BRCA1 pathway.

The biochemical changes that occur in these mouse tumors will help researchers understand the precise function of each gene. Microarray analysis of the activity of 12,000 other genes in the tumors should also uncover new genes that are important for tumor development and “derive important clues toward the eventual identification of potential drug targets for therapeutic intervention,” Dr. Efstratiadis says. “Although there are concerns as to the degree that mouse tumors can simulate the human disease, genetic manipulation of mice is extremely valuable for the study of basic cancer biology. The engineered animals are crucial for the dissection and exploration of causal relationships between effectors participating in tumorigenic signaling in the context of the whole experimental organism.”

These studies rely on tumor banks and technical expertise available in the pathology department and will exploit two advanced core facilities established in the Institute for Cancer Genetics with support from the departments of pathology and microbiology and the Herbert Irving Comprehensive Cancer Center. The genomics facility offers microarray analysis for global gene expression profiling, while the proteomics facility will feature high-performance mass spectrometry for protein identification.

Though several researchers in the project concentrate on a single breast cancer gene, epidemiologists realized 30 years ago that cancer only arises in the presence of synergy among several different defects in the cell. According to Dr. Baer, the institute’s ability to bring several specialties together should help develop a more holistic view of tumor development. “In the cell, tumor genes like PTEN, p53, BRCA1, and c-Myc are functionally interconnected,” he says. “Cancer arises from cooperative lesions in multiple cellular pathways, each of which are highly complex. Thus, a full understanding of the malignant process will require sophisticated tools and scientific collaborations – the goal of our institute is to foster such an interactive research setting for the study of human malignancy and with this project unravel basic mechanisms responsible for breast cancer.”

Unraveling basic mechanisms is also made more complicated by apparent subtypes, unlike colon cancer, which has a consistent set of mutations in most cases. BRCA1, which is mutated in many inherited cases, helps illustrate the complexity of breast cancer, which may turn out to be several diseases. “Usually when a tumor suppressor is found in familial cancer, we find significant numbers of sporadic cases also have the same dysfunctional gene. What’s surprising is, to this date, not a single case of sporadic breast cancer has been found with a BRCA1 mutation,” says Dr. Baer. “It’s possible that familial and sporadic cancers are different diseases, or possible that BRCA1 pathway is altered elsewhere and the two are similar biochemically. Nobody really knows.”

An answer to this, and other questions about breast cancer, should come in the next few years. “At end of the grant,” he says, “ we hope to know what has to go wrong for a breast cancer to develop.”