Estrogen Receptor Mutations and Changes in Downstream Gene Expression and Signaling

Abstract

Estrogens play a crucial role in regulating the growth and differentiation of breast cancers, with approximately two-thirds of all breast tumours expressing the estrogen receptor alpha (ERα). Therefore, therapeutic strategies directed at inhibiting the action of ERα by using antiestrogens such as tamoxifen, or reducing estrogens levels by using aromatase inhibitors (AIs), such as letrozole, anastrozole, or exemestane, are the standard treatments offered to women with ERα-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 due to alternative splicing or gene mutation have been identified. 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 which focus on more efficient blockade of receptor cross-talk.

D538G Mutation in Estrogen Receptor-α: A Novel Mechanism for Acquired Endocrine Resistance in Breast Cancer

“…Despite the central role of ERa in the development of breast cancer, mutation of ERa is a rare event (3). Two activating mutations of the ERa have been described previously, Y537N and K303R, and both occur in less than 1% of primary tumors (15)(16)(17). To our knowledge, the D538G mutation in ERa has not been described as yet.…”

“…Phosphorylation of Tyr-537 may inhibit activity of ERa, and substitution of it by Asn (Y537N) is associated with increased activity of the receptor (13,15). We examined the effect of 538G on phosphorylation of Tyr-537, using a phospho-Tyr-537-directed antibody.…”

Progress of Circulating Tumor Cells in Cancer Management

“…Heterogeneous protein function may foster tumor adaptation and may lead to drug resistance. 57,58 Thus, it is important to analyze tumor cells to obtain significant information. Considering the limitations of tumor biopsies, CTCs are expected to represent the full spectrum of the primary tumor and metastases and to play a role in guiding realtime drug selection.…”

La kinase IKKε

“…Bien que cette relation fonctionnelle n'ait pas été démontrée dans le contexte de cellules de cancer du sein, il est tentant de penser que l'inhibition de l'activation de CYLD via la phosphorylation par IKKε exerce un rôle de feed-back en amplifiant l'activation constitutive de IKKε. Les cancers du sein exprimant ERα (ERα + ) représentent 70 % des tumeurs [31]. Aucune corrélation n'a été observée entre la surexpression d'IKKε et l'expression d'ERα, mais IKKε active les fonctions de transactivation d'ER via la phosphorylation directe de la Ser167 déclenchant ainsi l'expression du gène CCND1 [12].…”

“…Le tamoxifène est prépondérant dans l'arsenal actuel contre le cancer du sein, cependant certaines tumeurs déve-lopppent une résistance à ce composé. Dans certains cas, cette résistance est associée à la phosphorylation d'ERα par diverses kinases [31] et il a été démontré que la phosphorylation de la Ser167 d'ERα par IKKε participe à la résistance au tamoxifène. En effet, l'interférence avec l'expression d'IKK rend les …”