Src inhibitors may prove beneficial in breast cancer therapy
Estrogen, which binds estrogen receptor alpha (ER-alpha), is a risk factor for breast cancer development. However, one-third of new breast cancers lack detectable ER-alpha. These ER-alphanegative cancers are more aggressive and have a worse prognosis than do ER-alphapositive breast cancers, and have been thought to be estrogen independent. In a study appearing online on July 12 in advance of publication in the August print issue of the Journal of Clinical Investigation, Joyce Slingerland and colleagues from the University of Miami shed further light on the mechanisms regulating ER-alpha expression levels during breast cancer.
In their study of 250 primary breast cancers, the authors found that ER mRNA levels overlap considerably between ER-alphapositive and ER-alphanegative breast cancers. This lack of correlation between ER-alpha mRNA and protein levels pointed to the existence of important post-transcriptional control of ER-alpha expression. They found that ER-alphanegative primary breast cancers and cell lines showed increased levels and/or activity of the protein Src, which cooperates with estrogen to activate ER-alpha breakdown via proteolysis. In line with this finding, Src inhibition was shown to impair estrogen-stimulated ER-alpha proteolysis. The data raise the possibility that for at least a subset of ER-alphanegative breast cancers, Src may stimulate estrogen-dependent ER-alpha degradation, resulting in a lack of ER-alpha detection, and more aggressive tumor growth. The authors conclude that their study provides a rationale for the use of Src inhibitors in breast cancer therapy.
TITLE: Src promotes estrogen-dependent estrogen receptor alpha proteolysis in human breast cancer
Joyce M. Slingerland
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone : (305) 243-7265;
Contact: Brooke Grindlinger
Journal of Clinical Investigation