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Breast Cancer

Description
Breast cancer happens when cells in the breast begin to grow out of control and can then invade nearby tissues or spread throughout the body. Large collections of this out of control tissue are called tumors. Theoretically, any of the types of tissue in the breast can form a cancer, but usually it comes from either the ducts or the glands.

Who is at Risk?
Breast cancer is the most common malignancy affecting women in North America and Europe. Every woman is at risk for breast cancer. Breast cancer is the second leading cause of death in American women behind lung cancer. The lifetime risk of any particular woman getting breast cancer is about 1 in 8 although the lifetime risk of dying from breast cancer is much lower at 1 in 28. Some factors that increase your risk of breast cancer that you cannot alter include being a woman, getting older, having a family history, being Caucasian, getting your periods young, having your menopause late, never having children or having them when you are older than 30, and having a genetic mutation. Certain factors which increase a woman's risk of breast cancer and can be altered including taking hormone replacement therapy, taking birth control pills, not breastfeeding, drinking 2 to 5 alcoholic drinks a day, being overweight, and not exercising.

Source: Abramson Cancer Center of the University of Pennsylvania
Breast Cancer Resources from OncologySTAT

Targeting Breast Cancer Metastasis
Breast cancer is a pressing public health concern because this cancer has a high propensity to metastasize and when it does, it can be deadly. Although science and medicine have made tremendous strides in early detection and successful treatment, breast cancer and melanoma, a highly metastatic form of skin cancer, still claim tens of thousands of lives a year - usually the end result of metastasis. TSRI Associate Professor Brunhilde Felding-Habermann, Ph.D. has been studying changes in gene expression that seem to control metastasis in human breast cancer. These changes affect an adhesion receptor called integrin avB3. Integrins help spreading cancer cells attach within the vasculature of new tissues.

When a cancer cell is in the circulation, it may have difficulty locking onto new tissues because of the interference of blood cells, plasma proteins, and the shear force produced by blood flow. Cancer cells need something like a hook to anchor themselves to a particular spot under these dynamic flow conditions, and integrins can be such hooks. Integrin avB3 seems to be needed for the cancer cells' arrest. Felding-Habermann has found a way to inhibit the attachment and remove the metastatic ability of breast cancer cells with special antibodies. She and her colleagues found antibodies that were originally produced by cancer patients and which bind selectively to the activated form of avB3 integrin. These antibodies inhibit the integrin's binding functions, which in turn prevents the cancer cells from attaching to platelets, and effectively blocks their ability to arrest in the blood stream. This study reveals that cancer patients can produce antibodies that may very actively interfere with metastasis. In fact, in Felding-Habermann's early in vivo tests, the antibodies effectively inhibited the metastasis of human breast cancer cells in a mouse model. Felding-Habermann and her colleagues are still in the very early stages of developing this technology, but it might be used as a vehicle to target a powerful anticancer drug to metastatic cells.

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Detecting Breast Cancer Proteins Through Chemical and Analytical Proteomics
TSRI Professor Benjamin Cravatt, Ph.D., has reported the latest results of a cutting-edge "proteomics" method. Cravatt and his colleagues looked at dozens of samples of human tumors from breast cancer patients, and then analyzed them with proteomics, the study of the expression, location, concentration, and activity of specific proteins. The scientists were able to detect human proteins that may be associated with breast cancer - including some that have never been associated with the disease. Proteomics has become an important tool in biology in the last decade because it offers the possibility of identifying proteins associated with specific diseases. These proteins can then potentially be used as markers for detection or prevention or as targets for the design of new drugs to treat the disease.

Cravatt has been developing an emerging proteomics technology called activity-based protein profiling. Activity-based protein profiling is a broad method for identifying which proteins are active in a given biological sample by subjecting these samples to chemical probes called "affinity labels", which have the ability to attach to the active sites of entire enzyme families in complex proteomes. Then the active proteins can be pulled out with the affinity probes and identified. The main drawback to the method has been that it lacks the sensitivity of some other approaches. But recently Cravatt combined his activity-based profiling with a highly sensitive proteomics method called multidimensional protein identification technology, or "MudPIT", which relies on mass spectrometry and was originally developed by the laboratory of TSRI Professor John Yates, Ph.D., with whom the Cravatt group collaborates. Basically, the two methods are applied in series - with the activity-based profiling returning pools of proteins and MudPIT then used to analyze these pools of proteins in more detail. Using these two methods together, Cravatt and his colleagues have found some known and novel markers of breast cancer pathogenesis. The combined method could potentially be applied to other human diseases to discover new markers currently evading detection by other methods.

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Applying New Cutting-edge Tools To Cell Metastasis
Associate Professor Richard Klemke, Ph.D., and Research Associate Yingchun Wang, Ph.D. of The Scripps Research Institute recently won a $135,000 grant from the Susan G. Komen Breast Cancer Foundation. They were selected for the highly competitive award because they are applying new cutting-edge tools to cell metastasis, one of the most important areas of breast cancer research. Klemke, Wang, and their colleagues are involved in research on aspects of the basic biology behind metastasis - trying to identify the signal transduction mechanisms that lead to the spread of breast cancer cells. What Klemke and Wang want to find are the key genes involved in breast cancer metastasis. In the end, they hope that they can knock out the metastatic signals and thus block the spread of cancer in humans.

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Protein Found To Control Tumor Growth In Certain Breast Cancers - Unexpected Discovery May Help Spark Search For New Treatments
Scientists from The Scripps Research Institute and the Xiamen University School of Life Sciences, Fujian, People's Republic of China, have uncovered a new and potentially important function for the protein Nod1, inhibiting the growth of estrogen sensitive human breast cancer cells. This protein was previously thought to play a role solely in the innate immune system's response to bacterial infection. In the new study, researchers showed for the first time that the protein, which is present in epithelial cells of the intestinal tract and lungs, is linked to the control of malignant cell growth. The study found that over-expression of the protein resulted in the nearly total inhibition of estrogen-dependent tumor growth in mice, and the reduction of estrogen-induced proliferative responses in vitro. In stark contrast, significant tumor growth occurred when Nod1 was absent. The study was led by Richard J. Ulevitch, Ph.D., a professor and chairman of the Scripps Research Department of Immunology. The unexpected findings offer the first real evidence that this pathway may regulate tumor growth and suggest a potentially new mechanism for controlling this type of breast cancer. Unraveling the intricate mechanisms of this previously unknown pathway opens up the potential for future development of novel therapeutics, and will hopefully stimulate researchers to take a fresh look at the Nod1 protein.

In the study, researchers looked at a number of biological processes where Nod1-dependent apoptotic (programmed cell death) pathways were a critical component, including the regulation of tumor cell growth where the failure of malignant cells to undergo cell death led to tumorigenesis. Cells derived from the human breast cancer epithelial cell line MCF-7 - the cellular model for estrogen sensitive breast cancer tumors - were used to induce tumor growth in severe combined immunodeficiency (SCID) mice. An over-expression of Nod1 in MCF-7 cells resulted in the inhibition of estrogen-dependent tumor growth in the SCID mice and a reduction of estrogen-induced proliferative responses in vitro. Moreover, scientists found that the tumors diminished rapidly in these mice, becoming virtually undetectable by the end of the experiment. In MCF-7 cells where Nod1 was absent, the tumors flourished. In addition, there was an increased sensitivity to estrogen-induced cell proliferation and a failure to undergo Nod1-dependent apoptosis in vitro. Taking these initial findings one step further, researchers implanted estrogen pellets in the SCID mice to accelerate tumorigenesis. In those mice receiving Nod1 cell lines tumor growth did not occur even in the presence of estrogen pellets, indicating that Nod1 acts as an effective cellular brake on estrogen-dependent tumor growth. In addition, the presence of Nod1 reduced the expression of the naturally occurring estrogen receptor in vitro, further indication that the protein mediates the sensitivity of hormone-dependent breast cancer cells to tumorigenesis. The evidence uncovered in this study provides new insights into the physiological functions of Nod1 and supports the contention that there is a clear link between Nod1 and estrogen sensitivity in these cells. Future studies will assess the relationship between the pathway uncovered in breast cancer and other hormone sensitive malignancies. Those studies may help in the development of new therapeutic approaches with the potential to stabilize or even eradicate hormone-sensitive tumors.

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New Findings Could Improve Anti-Estrogen
Breast Cancer Therapy
Scientists at The Scripps Research Institute, working in collaboration with researchers from Creighton University and the Medical College of Zhejiang University (P.R. China), have discovered a novel variant of a known human estrogen receptor (hER-a66). The new variant-called hER-a36-"functions very differently" from hER-a66 in response to estrogen signaling, the study said, inhibiting key estrogen-dependent and estrogen-independent activities of hER-a66 and stimulating cell growth. Because of these differences, this new estrogen receptor could become an important therapeutic target and may play a further signaling role in other estrogen target tissues, including uterus and prostate tissues.These new findings could significantly advance the understanding of the effects of estrogen in breast cancer and point the way towards new and potentially more effective treatments of the disease.

Estrogen has long been linked to the development of breast cancer, both through the stimulation of breast cell growth, which can lead to mutation, and through estrogen metabolism, which can interfere with apoptosis and DNA repair. Estrogen receptors mediate the majority of the actions of estrogen, including the metastatic growth of breast cancer cells, and are an important marker in therapy; readable levels of estrogen receptor proteins are expressed in a large portion of human breast cells. Professor Thomas F. Deuel, M.D., a Scripps Research scientist, participated in the study. The estrogen and anti-estrogen signaling pathways mediated by this new receptor could explain why some breast cancers grow worse or become resistant to anti-estrogen therapy, specifically the drug tamoxifen, which blocks estrogen signaled responses through ER-a66 in breast tissue. According to the National Cancer Institute, anti-estrogen therapy is most often used in postmenopausal women whose tumors grow in response to the hormone.

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Researchers Unveil Strategy For Creating Actively Programmed Anti-Cancer Molecules
Scientists at The Scripps Research Institute and The Skaggs Institute for Chemical Biology have developed a unique assembly strategy to produce an anti-cancer targeting antibody, an approach that combines the merits of small molecule drug design with immunotherapy. Among the potential therapeutic advantages is a dramatically increased circulatory half-life of the compound, which could give patients greater exposure to the benefits of any treatment. The new study achieved a significant enhancement of the treatment of metastatic breast cancer in animal models. The study showed the new hybrid compound remained in circulation for a week. In comparison, the small molecule drug was cleared in a matter of minutes.Although the study focused specifically on breast cancer, these new findings could have broad application in the treatment of a number of other cancers, potentially increasing the efficacy of a number of existing or undeveloped small molecule therapies. Subhash C. Sinha, Ph.D., associate professor in the Scripps Research Department of Molecular Biology and the Skaggs Institute for Chemical Biology, led the research with Scripps Research President Richard A. Lerner, M.D., Lita Annenberg Hazen Professor of Immunochemistry, Cecil H. and Ida M. Green Chair in Chemistry, and a member of the Skaggs Institute for Chemical Biology.

In the study, the scientists created what is known as a "chemically programmed antibody" by using small cell-targeting molecules and a non-targeting catalytic monoclonal aldolase antibody in a novel self-assembly strategy. Antibodies are proteins produced by immune cells that are designed to recognize foreign pathogens harmful to the body; monoclonal antibodies are produced in the laboratory from a single cloned B-cell, the immune system cell that makes antibodies. By bringing together chemistry and biology, the approach of the scientists provides a way to break the traditional one antibody-one target axiom of immunochemistry. This new hybrid technology offers great possibilities for the enhanced treatment and diagnosis of a variety of diseases, including cancer.

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Scripps Florida Study Could Lead To More Effective Therapies For Breast Cancer, Other Disorders
Scientists at The Scripps Research Institute's Scripps Florida facilities have developed a novel method to help determine the probable effectiveness of drug candidates for the treatment of estrogen-dependent disorders such as breast cancer and osteoporosis. These findings could lead to the development of a new generation of optimized selective estrogen receptor modulators (SERMs) with specific binding modes on the target. With new drug candidates, one must make certain that there is the right interaction with the target. Patrick Griffin, Ph.D., Scripps Research professor and chair of molecular therapeutics and director of the Translational Research Institute at Scripps Florida, led the study. One needs to be able to accurately predict the full range of activity of that potential candidate. Griffin's single biochemical test compares new drug candidates against currently available SERMs, so that one can determine, in rapid fashion, if the new compound is worth pursuing. Traditional drug discovery programs involve multiple complex assays to determine the tissue selectivity of potent modulators or ligands (molecules that bind to specific sites on a target protein) for estrogen receptors. Unfortunately, translating these extensive, very time consuming laboratory tests into clinically relevant tissue selectivity has been limited, the study said. The technology at Scripps Florida has enormous potential in the development of new treatments for breast cancer - and for diseases beyond cancer, including cardiovascular disease and osteoporosis. As a single biochemical assay, this new platform can replace the current load of expensive, multiple cell-based procedures that may take weeks to achieve useful results. In rapid screening mode, Griffin noted, the new test can review 40 to 50 compounds per week.

Given the relative slowness of traditional studies, anything that can help rationally filter potential compounds that may be important for women's health is a plus. The scientists looked at compounds that affected estrogen receptors, important regulators of the reproductive system that help maintain skeletal and cardiovascular tone. Since estrogen is involved in diseases such as breast cancer and osteoporosis, estrogen receptors are targeted therapeutically for these conditions. In the study, Scripps Florida scientists used hydrogen/deuterium mass spectrometry to measure the interaction of various ligands with the estrogen receptor. A mass spectrometer determines the mass of a molecule by measuring the mass-to-charge ratio of its ions. Hydrogen/deuterium mass spectrometry is a mass-encoded technique that provides a sensor for the local environment of the ligand binding area in a protein. The results showed the specific regions of the protein that interact with the ligand and the structural changes that result from that interaction. Using well characterized compounds as controls, the new test offers an accurate prediction of how such a new compound will perform in animal models, a critical advantage if one wants to optimize a compound for a specific response. Using current treatments as model molecules or controls, Griffin's test allows one to filter out those candidates that have different interactions with the target receptor and focus on those that have preferred interactions. The new test is highly sensitive, rapid, and can be done under physiologically relevant conditions. Griffin and his colleagues are able to distinguish between structurally similar compounds, even those with subtle differences, in a meaningful way.

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Scientists Pinpoint New Cancer Stem Cell Links to Chemotherapy Resistance
Using a multifaceted approach, scientists from The Scripps Research Institute have successfully identified more than 40 new therapeutic targets in breast cancer stem cells. Current research supports the idea that tumors are organized in a hierarchy of various cell populations with different biological properties, and that the potential for sustained tumor formation and growth resides exclusively in a small number of tumor cells called cancer stem cells. The new study demonstrates a novel strategy for the discovery of therapeutic targets in cancer stem cells that could lead to the development of potential therapies. The study also sheds light on one mechanism of cancer stem cell drug resistance. The study offers fresh insights into breast cancer stem cell populations. Kim Janda, Ph.D., Ely R. Callaway Jr. Professor of Chemistry, member of The Skaggs Institute for Chemical Biology, and director of the Worm Institute of Research and Medicine (WIRM), at Scripps Research, led the study. Using a multifaceted approach, Janda and his colleagues compared cancer stem cells, which live within the general cancer cell population and are resistant to chemotherapy, to non-cancer stem cells. As a result, they were able to identify 41 proteins that play a role in drug resistance and, possibly, tumorgenicity in breast cancer. Cancer stem cells are a small subpopulation of cells found in blood and solid tumors that have been shown to possess stem cell characteristics, such as the ability to proliferate. Interest in cancer stem cells continues to grow as a fundamental understanding in their role in the development and progression of the disease grows.

To better understand the importance of breast cancer stem cells, Janda and his colleagues set out to characterize the cancer stem cell population from two breast cancer cell lines in both in vitro studies and in animal models. The team used a quantitative proteomics approach that combined cell sorting and stable isotope labeling with amino acids in cell culture (SILAC) with mass spectrometry to compare and identify proteins with different expression profiles between the cancer stem cell population and non-cancer stem cell population. SILAC is a basic approach for in vivo label insertion into proteins for mass spectrometry quantitative proteomics. In addition to the other potential targets, proteomic analysis of the side population cells revealed an increase in the expression of TB4 (beta thymosin), a small intracellular protein involved in cell movement. Increased expression of this protein has been found in various tumors, including breast, ovary, uterus, colon and thyroid. TB4 expression has been studied in breast cancer cells, and the levels of beta thymosins in tumor tissues have been suggested as a potential diagnostic tumor marker. When treated with the chemotherapy drug Doxorubicin (91.2% and 99.5%, respectively), the cancer stem cells showed a significantly greater survival rate than non-cancer stem cells after 24 hours. Similar results were obtained with Methotrexate and 5-Flourouracil, other widely used chemotherapies. The team used silencing RNA to block TB4 to see if breast cancer cell death increased with paclitaxel and doxorubicin treatment. Cell death did increase, implicating TB4 in the drug resistance of cancer stem cells.

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