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-alpha–negative cancers are more aggressive and have a worse prognosis than do ER-alpha–positive breast cancers, and have been thought to be estrogen independent.
In a new study, 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-alpha–positive and ER-alpha–negative 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-alpha–negative 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-alpha–negative 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.
Src promotes estrogen-dependent estrogen receptor alpha proteolysis in human breast cancer, Joyce M. Slingerland
University of Miami Miller School of Medicine, Miami, Florida