Mechanisms that Increase Stability of Estrogen Receptor Alpha in Breast Cancer

Estrogen receptor alpha (ER) is a transcriptional regulator that controls the expression of genes related to cellular proliferation and differentiation in normal mammary tissue. However, the expression, abundance, and activity of this receptor are increased in 70% of breast cancers. The ER upregulation is facilitated by several molecular mechanisms, including protein stability, which represents an important strategy to maintain an active and functional repertoire of ER. Several proteins interact and protect ER from degradation by the ubiquitin-proteasome system. Through diverse mechanisms, these proteins prevent polyubiquitination and degradation of ER, leading to an increase in ER protein levels; consequently, estrogen signaling and its physiologic effects are enhanced in breast cancer cells. Thus, increased protein stability seems to be one of the main reasons that ER is upregulated in breast cancer. Here, we highlight findings on the proteins and mechanisms that participate directly or indirectly in ER stability and their relevance to breast cancer.