Mechanisms of estrogen receptor-α upregulation in breast cancers

The most critical step for initiation and progression of estrogen receptor-alpha (ER alpha)-positive breast cancers is thought to be upregulation of ER alpha expression. There are several factors involved in this mechanism, i.e., increased promoter activity of the ER alpha gene (ESR1) at the transcriptional level, ESR1 gene amplification, and diminished degradation of ER alpha protein through ubiquitination and proteasomal pathways. Mediating these factors, ER alpha protein levels seem to be controlled, although the details of the mechanism remain to be clarified. In addition, for upregulation of estrogen signaling, functional changes in its action in cancer cells originating from normal epithelial cells, i.e., estrogen stimulation, which then leads to proliferation of ER alpha-positive cancer cells, has been recognized, but this action has not been observed in normal epithelial cells. These alterations are therefore likely to contribute to the pathogenesis of ER alpha-positive breast cancers.