CSHL scientists identify new drug target against virulent type of bre...(ty and fortifies tumor cells against Erb...)

Date:8/25/2008

ty and fortifies tumor cells against ErbB2-targeting drugs. "Our results might explain why the strategy of using ErbB2 inhibitors alone to treat breast cancers has fallen short," noted Dr. Muthuswamy. "These findings may also suggest a way to treat patients with advanced ErbB2-positive tumors and those who've developed resistance to ErbB2 inhibitors an idea that we're eager to test."

ErbB2 and Brk go hand-in-hand

ErbB2 is a member of a family of enzymes called receptor tyrosine kinases -- cell-surface molecules that goad cells into proliferating when they sense growth cues in the environs of cells that express them. It turns out that the over-production of ErbB2 in breast cancers is due to a gene mutation that results in the accumulation of multiple copies of the erbB2 gene.

Other genes that undergo such "amplification" due the duplication of DNA segments include brk, which is the gene that instructs cells to manufacture the enzyme Brk. This enzyme is absent in healthy cells but is found at high levels in a majority of breast cancers. As some of these cancers also over-express ErbB2, the CSHL team wondered whether the offending genes, erbB2 and brk, are mutated in tandem, or "co-amplified." This idea in turn raised the possibility that the proteins encoded by these genes are also co-activated and feed into the same proliferation-promoting pathway.

The team checked breast cancer tissue from more than two hundred patients for variations in the number of copies of both genes and found that they were both amplified abnormally in a significant number of these samples. Re-analyzing the samples for the expression levels of both genes revealed that "co-amplified" genes were also "co-overexpressed" -- they were the source of abnormally high levels of their corresponding proteins.

Brk acts as an accelerator of proliferation

Further experiments by Muthuswamy's team revealed that although Brk does not indu
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Contact: Peter Tarr tarr123@gmail.com 516-367-8455 Cold Spring Harbor Laboratory Source:Eurekalert

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