Dana-Farber's Judy Garber, MD, MPH, will present the study's data (Abstract 508) - on behalf of her colleagues at Yale University School of Medicine and more than 30 institutions and medical practices in the Cancer and Leukemia Group B consortium, a clinical research network organized by the National Cancer Institute - during an oral presentation on Sunday, May 15, at 8 a.m., Level 2, Hall A2.
The study involved more than 300 women receiving tamoxifen as "adjuvant" therapy - given after a new breast cancer diagnosis to prevent recurrence. Researchers focused on a blood-clotting protein called Factor V. Previous studies had shown that women with a specific Factor V gene mutation - which gives rise to an abnormal version of the protein, known as Factor V Leiden (FVL) - are at increased risk for blood clots when pregnant or taking oral contraceptives or estrogen replacement therapy.
In the new study, researchers found that women who had blood clots while taking tamoxifen were almost four times as likely to have an FVL mutation as were those who did not have blood clots. The results suggest that testing women in advance for FVL mutations may enable physicians to identify some women who should either use alternatives to tamoxifen or, if good alternatives are not available, use a blood thinner while taking tamoxifen.
"Other factors contributing to blood clot risk must also be considered in the decision to recommend tamoxifen to generally healthy women, including a history of previous blood clots, obesity and planned surgery," says Garber. "But FVL testing can now be used to help make this powerful medication safer for some women who need it for breast cancer treatment or prevention."
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To investigate CD147's part in the activity of gamma-secretase, the researchers used targeted RNA to silence CD147 in cell cultures. The four previously known components of the gamma-secretase complex, as well as the APP protein on which they operate, were unaffected by this silencing. But when CD147 was silenced, the production of amyloid beta peptides increased markedly.
The researchers established that the native form of gamma-secretase, incorporating CD147, appears in other cell lines, including kidney cells and neuronal cells, and is not unique to HeLa cells (which are derived from cervical cancer). CD147 itself is found in many contexts besides gamma-secretase, but only as a part of gamma-secretase does it regulate the production of A-beta peptides and thus amyloid plaques.
Just how does CD147 do what appears to be its normal job of preventing excessive production of A-beta 42 peptides, and what causes it to fail? Zhou says, "We know CD147 is a regulatory subunit of gamma-secretase, but we don't know how it works. As yet we don't know its mode of action with respect to the other members of gamma-secretase and its substrates. Determining this mode of action is a key goal of our future efforts."
About 25 amino-acid residues make up the length of CD147 that crosses through the cell membrane, one of which, glutamic acid, has net electrical charge. Such an unlikely placement for a charged residue suggests that this region of CD147 may seek to align with another protein's oppositely charged region, perhaps that of Psn-1. Disruption of this transmembrane teamwork could lead to increased production of amyloid beta peptides which, in turn, may result in the amyloid beta plaque formation that is a hallmark of Alzheimer?s disease.
"The answer to how the components of gamma-secretase components fit together inside the cell membrane has to wait for high-resolution structural work," says Zhou, "and for that we first have to make enough of the native complex to make crystals."
Bing Jap adds, "Determining the atomic structure of the gamma-secretase complex, including CD147, is the next crucial step in understanding the molecular mechanisms by which the substrates are cleaved in various forms - and the next crucial step to designing Alzheimer's disease therapeutics."
"CD147 is a regulatory subunit of the ?-secretase complex in Alzheimer's disease amyloid ?©?¬-peptide production," by Shuxia Zhou, Hua Zhou, Peter J. Walian, and Bing K. Jap, appears in the online early edition of the Proceedings of the National Academy of Sciences.
Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California.
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