
JACKSONVILLE, Fla. — A single gene that promotes initial development of the most common form of lung cancer and its lethal metastases has been identified by researchers at Mayo Clinic in Florida. Their study suggests other forms of cancer may also be driven by this gene, matrix metalloproteinase-10 (MMP-10). The study, published in the journal PLoS ONE on April 24, shows that MMP-10 is a growth factor secreted and then used by cancer stem-like cells to keep themselves vital. These cells then drive lung cancer and its spread, and are notoriously immune to conventional treatment. The findings raise hope for a possible treatment for non-small cell lung cancer, the leading cause of U.S. cancer deaths. Researchers discovered that by shutting down MMP-10, lung cancer stem cells lose their ability to develop tumors. When the gene is given back to the cells, they can form tumors again. The power of this gene is extraordinary, says senior investigator Alan Fields, Ph.D., the Monica Flynn Jacoby Professor of Cancer Research within the Department of Cancer Biology at Mayo Clinic in Florida. "Our data provides evidence that MMP-10 plays a dual role in cancer. It stimulates the growth of cancer stem cells and stimulates their metastatic potential," he says. "This helps explain an observation that has been seen in cancer stem cells from many tumor types, namely that cancer stem cells appear to be not only the cells that initiate tumors, but also the cells that give rise to metastases." Dr. Fields says the findings were unexpected, for several reasons. The first is that the cancer stem cells express MMP-10 themselves, and use it for their own growth. Most of the known members of the matrix metalloproteinase genes are expressed in the tumor's microenvironment, the cells and tissue that surround a tumor, he says. The enzymes produced by these genes are involved in breaking down the microenvironment that keeps a tumor in place, allowing cancer cells to spread, which is why other genes in this family have been linked to cancer metastasis. "The fact that a gene like MMP-10, which codes for a matrix metalloproteinase that has been linked to metastasis, is actually required for the growth and maintenance of cancer stem cells is very surprising. One would not have predicted that such a gene would be involved in this process," Dr. Fields says.
A new class of molecular mutation, in various forms of breast cancer, has been discovered by Mayo Clinic researchers in Florida. This finding may shed new ...
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JACKSONVILLE, Fla. — April 10, 2012. Mayo Clinic researchers have discovered a new class of molecular mutation in various forms of breast cancer, a finding that may shed new light on development and growth of different types of breast tumors. Called fusion transcripts, the mutated forms of RNA may also provide a way to identify tumor subtypes and offer new strategies to treat them, investigators say. Their study, published in the April 15 issue of Cancer Research, is the first to systematically search for fusion genes and fusion transcripts linked to different types of breast tumors. Oncologists currently recognize three basic types of breast tumors — estrogen-receptor (ER)-positive, HER2-positive, and triple negative. "But breast cancer is much more complex than indicated by these three subtypes, and one of the challenges of treating the disease is to identify gene markers that predict how a tumor will respond to a specific treatment," says senior investigator Edith Perez, M.D., deputy director of the Mayo Clinic Comprehensive Cancer Center in Florida and director of the Breast Cancer Translational Genomics Program, which involves researchers at all three Mayo Clinic campuses. "The discovery of subtype-specific fusion transcripts in breast cancer represents a step in this direction," she says. "Our findings indicate that fusion transcripts are much more common in breast cancer than had been realized. They represent a new class of mutation whose role in breast cancer is not understood at all." "Fusion transcripts have the power to produce proteins that are relevant to tumor development, growth, and sensitivity to treatment, so we may have a brand new set of genomic changes that may help us understand, and treat, breast cancer in a new way," says E. Aubrey Thompson, Ph.D., professor of Biology at Mayo Clinic's Comprehensive Cancer Center, and co-director of the Breast Cancer Translational Genomics Program. "This is a novel discovery that will now require additional investigation," he says. "We need to understand what these fusion transcripts and proteins are doing." Fusion transcripts are created when chromosomes break apart and recombine, an event that commonly occurs in cancer cells. During this process, fusion genes are created when two halves of normal genes become linked. Fusion genes (DNA) create fusion transcripts (RNA), which then produce fusion proteins. "Mistakes are made," Dr. Thompson says. "That is one of the salient properties of tumor cells, because they are defective in repairing damage to their genes." "These mutated proteins may have an entirely new, cancer-promoting function, or they may interfere with normal cellular functions." Fusion transcripts are common in blood cancers, such as leukemia and lymphoma. Before this discovery, however, few were found in solid cancers such as breast tumors. Because fusion genes, transcript, and protein are generally found only in tumors, they make ideal biomarkers to identify tumor cells, Dr. Perez says.
The Breast Cancer Genome Guided Therapy Study (BEAUTY Project) will help physicians tailor chemotherapy to breast cancer patients based on their individual genomes and the ...
ROCHESTER, Minn. — April 9, 2012. The Breast Cancer Genome Guided Therapy Study (BEAUTY Project) will help physicians tailor chemotherapy to breast cancer patients based on their individual genomes and the genomes of their tumors. Mayo Clinic researchers will obtain three whole genome sequences: one from the patients' healthy cells before treatment, and two tumor genomes – one before chemotherapy and one after. Patients will be paired with mouse "avatars" that will help physicians identify the best treatment for each person. "What is so exciting about this study is that it has the potential to really bring individualized medicine to our patients," says Matthew Goetz, M.D., Mayo oncologist and study co-leader. "It will transform how we conduct breast cancer research and how drug therapies are delivered to women with breast cancer." In phase one of the BEAUTY Project, researchers will study the first 200 participants to look for common mutations that allow some tumors to adapt and thrive during chemotherapy. This information will help doctors identify new drugs and treatment strategies. Women diagnosed with "high-risk" cancers who are scheduled to receive standard chemotherapy before surgery will have their healthy genome and their breast cancer tumor cells sequenced before treatment, and then receive the commonly prescribed chemotherapy to shrink the tumor. At surgery, the residual cancer tumor cells will be sequenced again to evaluate how they have mutated and adapted to chemotherapy. In addition, patients' tumor tissue will be kept alive by implanting cell lines in immune-compromised mice — before and after chemotherapy. The use of these mouse "avatars'' will let researchers study the effects of chemotherapy on individual patient tumors and identify the best treatment, without risk of harm to the patient. "Patients are pleased after definitive breast surgery to be cancer free," says Judy Boughey, M.D., a Mayo breast surgeon and study co-leader. "Unfortunately, a subset of high-risk patients still may experience recurrence, even months or years later. We designed this study to give those patients hope that our ability to decode the genome of every patient might give us new tools to treat cancer."
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