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Guilt by Association: The Complexity of Breast Cancer
Posted December 17, 2003
Ramin Shiekhattar, Ph.D., The Wistar Institute, Philadelphia, Pennsylvania

Researchers have identified BRCA1 and BRCA2 as genes that can be changed or mutated leading to the development of breast cancer. These genes are associated with an increased risk of familial breast cancer. Proteins are synthesized from genes and carry out the instructions contained within the DNA. Alterations at the genomic level lead to a protein process gone awry. By examining protein complexes rather than just one protein, Dr. Ramin Shiekhattar and co-investigators at the Wistar Institute hope to discover novel proteins that may be associated with both familial and sporadic incidences of breast cancer. They hypothesize that proteins "guilty by association" with BRCA1 may assist in cancer progression. To analyze BRCA1 containing protein complexes, Dr Shiekhattar and his colleagues combined modern molecular biology techniques with classic biochemical studies. By labeling BARD1 (a protein known to interact with BRCA1) with a molecular tag, the scientists were able to use it as a hook to fish out other proteins in the BRCA1 complex. Members of the protein complex could then be isolated by chromatography and identified using mass spectrometry. The proteins found to associate with the new complex called BRCC (BRCA1 and BRCA2 containing complex) were BRCA1, BRCA2, RAD51, BRCC36, and BRCC45. The last two proteins, BRCC36 and BRCC45, are novel proteins. Exploring the function of the complex, the researchers were able to demonstrate a ligase activity of BRCC. The complex plays a regulatory role in DNA repair by targeting for degradation, proteins that are known to activate the cell proliferation cycle. By halting cell proliferation, BRCC acts as a stopgap measure to allow the cell to repair any damage to the DNA following adverse events such as ionizing radiation prior to cell division. If one protein of the complex is mutated and does not function properly, BRCC may fail in its role, thus leading to cell division without DNA repair, one step in the process of carcinogenesis. Proteins linked to the complex are therefore suspects in the development of breast cancer and are "guilty by association" according to Dr. Shiekhattar. Understanding how the proteins within the holoenzyme complex of BRCC function may lead to new insights in breast cancer research as well as new targets for future therapies.

Publications:

Dong Y, Hakimi M, Chen X, Kumaraswamy E, Cooch NS, Godwin A, and Shiekhattar R. 2003. Regulation of BRCC, a Holoenzyme Complex Containing BRCA1 and BRCA2, by a Signalosome-like Subunit and Its Role in DNA Repair. Molecular Cell 12:1087-1099.

Link:

Abstract: Deciphering the Molecular Mechanism of Breast Cancer

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Tumor-Mediated Formation of Lymphatic Vessels: Building Roads Out
Posted April 30, 2003
Mihaela Skobe, Ph.D., Mt. Sinai School of Medicine

Over the last decade, considerable attention in the field of cancer research has focused on angiogenesis, or formation of new blood vessels. Current drug design strategies have centered on ways to hold this process in check, thereby limiting or eliminating the blood supply to tumors. Breast Cancer Research Program Concept awardee, Dr. Mihaela Skobe, has discovered that angiogenesis is not the only vessel formation process occurring in the tumor microenvironment. Lymphangiogenesis, or formation of lymphatic vessels, is also an active process mediated by tumors. This finding is significant because the lymphatic system is the main conduit by which breast cancer metastasis occurs. Historically, controversy has existed as to whether tumor lymphangiogenesis occurs; however, work from Dr. Skobe's lab puts this debate to rest. The group has also discovered that a specific protein, called VEGF-C, appears to be involved. When breast tumor cells that over-produce this protein are implanted into mice, lymphangiogenesis within the tumors increases, as well as the incidence of metastasis to the lymph nodes and lungs. Additionally, the more lymphangiogenesis, the more metastasis, further underscoring the importance of the lymphatic vessel system in tumor cell dissemination. This novel discovery has important implications since it offers a new target for therapy development to control the spread of breast cancer.

Publications:

Skobe M, et al. 2001. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med. 7:192-198.

Swartz MA and Skobe M. 2001. Lymphatic function, lymphangiogenesis, and cancer metastasis. Microscopy Res. 55:92-99.

Cassella M and Skobe M. 2002. Activation of lymphatic vessels in cancer. Ann. NY Acad. Sci. 979:120-130.

Podgrabinska S, et al. 20002. Molecular characterization of lymphatic endothelial cells. Proc. Natl. Acad. Sci. USA. 99:16069-16074.

Link:

Abstract: Significance of Lymphangiogenesis for Metastatic Spread of Breast Cancer

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Alternative Medicines Open New Doors in Traditional Breast Cancer Research: Targeted Therapy for Tumor Angiogenesis and Cancer
Posted January 3, 2003
Mamoru Shoji, M.D., Dennis C. Liotta, Ph.D. and James P. Snyder, Ph.D., Emory University

A resurgent interest in age-old remedies for ailments has spurred the medical research community to explore alternative methods of treatment. Therapies exploiting the properties of curcumin, the active ingredient in the spice tumeric, have shown increased promise in the last few years. Recently, researchers reported curcumin has a marked antitumor effect on cancers of the skin, colon, prostate, and breast. Another method by which curcumin works is through blocking the synthesis of factors known to participate in a process called angiogenesis, the generation of new blood vessels. This mechanism of action cuts off the blood supply to the tumor cells, which leads to cell death. Drs. Shoji, Liotta, and Snyder of Emory University (Atlanta, Georgia) are developing synthetic analogs of curcumin for delivery specifically to tumors of the breast and to the blood vessels that nourish the tumors. In their ongoing study, a curcumin analog has been linked chemically to a carrier molecule that targets breast cancer cells and tumor-associated blood vessels (vascular endothelial cells). The synthetic complex kills the tumor but does not kill normal breast cells and normal blood vessels (vascular endothelial cells) in tissue culture. Results demonstrate an astounding 10-fold potency in antitumor activity over the chemotherapeutic agent cisplatin. The outcome suggests that by using a carrier-tagged analog of curcumin, tumor cells and the blood vessels that feed tumors can be selectively attacked and killed, overcoming toxic effects of other non-specific anti-cancer and anti-angiogenic agents. Tumor-directed therapies have the potential of decreasing the side effects of chemotherapy regimens, while alternative medicines give a fresh look to an ever-pressing problem. The marriage of these two approaches may be a powerful new tool in the fight against breast cancer.

Link:

Abstract: Targeted Delivery of Novel Antiangiogenic Agents in Breast Cancer

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