Dasatinib (Sprycel)

[gdpawel]

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 study published in the August 2007 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-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.

Source: The Journal of Clinical Investigation