ER Re-expression and Re-sensitization to Endocrine Therapies in ER-negative Breast Cancers

Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ER alpha in breast cancers is an important prognostic indicator. About 30-40% of breast cancers lack detectable ER alpha protein. ER alpha- breast cancers are resistant to endocrine therapies and have a worse prognosis than ER alpha+ breast cancers. Since expression of ER alpha is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ER alpha- phenotype and develop interventions to restore ER alpha expression in ER alpha- breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ER alpha expression and in these cases; demethylation of the ER alpha promoter or treatment with HDAC inhibitors shows promise in restoring ER alpha expression in ER alpha- breast cancers. Two additional potential mechanisms underlying generation of the ER alpha- phenotype involve E6-AP and Src, both of which have been shown to be elevated in ER alpha- breast cancer and can drive the proteasomal degradation of ER alpha. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ER alpha- phenotype and that inhibition of MAPK activity can cause re-expression of the ER alpha and restore sensitivity to endocrine therapies. Given the challenges in treating ER alpha- breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ER alpha are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ER alpha- breast cancers.