Estrogen receptor mutations and changes in downstream gene expression and signaling

Estrogens play a crucial role in regulating the growth and differentiation of breast cancers, with approximately two thirds of all breast tumors expressing the estrogen receptor alpha (ERalpha). Therefore, therapeutic strategies directed at inhibiting the action of ERalpha by using anti-estrogens such as tamoxifen, or reducing estrogens levels by using aromatase inhibitors, such as letrozole, anastrozole, or exemestane, are the standard treatments offered to women with ERalpha-positive cancer. However, not all patients respond to endocrine therapies (termed de novo resistance), and a large number of patients who do respond will eventually develop disease progression or recurrence while on therapy (acquired resistance). Recently, variant forms of the receptor have been identified owing to alternative splicing or gene mutation. This article reviews these variant receptors and their clinical relevance in resistance to endocrine therapy, by addressing their molecular cross-talk with growth factor receptors and signaling components. Understanding the complexity of receptor-mediated signaling has promise for new combined therapeutic options that focus on more efficient blockade of receptor cross-talk.