Scientists have determined the shape of a receptor that is centrally involved in the development of hormone-sensitive breast cancers according to a report in the April issue of Nature Structural & Molecular Biology. The findings suggest that blocking the activity of this receptor could slow the progression of hormone sensitive breast cancers.
One in seven women will develop invasive breast cancer in her life. About two thirds of these cancers are induced by hormones such as estrogen, and treatments have focused on blocking its effect or lowering its level in the patient. The most common anti-estrogen drug is tamoxifen, but it is not always effective in women with advanced breast cancer.
Human liver receptor homolog 1 (LRH-1) is known to play a role in the development of hormone-sensitive breast cancer, and it is also involved in cholesterol and lipid metabolism. Whether the action of LHR-1 in these processes depends on the binding of small molecules to the receptor has not been clearly established -- until now. Matthew Redinbo (University of North Carolina) and colleagues used X-ray crystallography and biochemistry to examine the structure and mechanism of action of LHR-1.
Structural analysis reveals that LHR-1 binds to lipid molecules. Most important, mutations that affect this binding interaction decrease receptor activity in human breast cancer cells. Previous work had shown that LHR-1 controls the level of another protein, aromatase, in breast preadipocytes. Aromatase is involved in synthesis of estrogen which fuels local tumor growth. These observations and the new data from Redinbo and colleagues suggest that the receptor is a new target for small molecule compounds other than estrogen blockers, designed to decrease the activity of LHR-1 and thereby the levels of estrogen in the cell.
Matthew Redinbo (University of North Carolina, Chapel Hill, NC, USA)
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(C) Nature Structural & Molecular Biology press release.
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