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