Memo interacts with c-Src to control Estrogen Receptor alpha sub-cellular localization.

Anna Frei,Ivan Nalvarte,Jan-Åke Gustafsson,Ingrid Lund,Gwen Macdonald,Nancy E Hynes

doi:10.18632/oncotarget.10856

Abstract

Understanding the complex interaction between growth factor and steroid hormone signaling pathways in breast cancer is key to identifying suitable therapeutic strategies to avoid progression and therapy resistance. The interaction between these two pathways is of paramount importance for the development of endocrine resistance. Nevertheless, the molecular mechanisms behind their crosstalk are still largely obscure. We previously reported that Memo is a small redox-active protein that controls heregulin-mediated migration of breast cancer cells. Here we report that Memo sits at the intersection between heregulin and estrogen signaling, and that Memo controls Estrogen Receptor alpha (ERα) sub-cellular localization, phosphorylation, and function downstream of heregulin and estrogen in breast cancer cells. Memo facilitates ERα and c-Src interaction, ERα Y537 phosphorylation, and has the ability to control ERα extra-nuclear localization. Thus, we identify Memo as an important key mediator between the heregulin and estrogen signaling pathways, which affects both breast cancer cell migration and proliferation.

Highlights

Estrogen (E2) binds and activates estrogen receptors (ERs) to enter the nucleus and regulate the expression of genes involved in cell survival, proliferation and differentiation [1]
E2 treatment only gave a ~2.5 fold increase in Cyclin D1 expression (Figure 1E), we could detect a significant enrichment of ERα at the estrogen response element (ERE) promoter site of this gene (Figure 1F)
Endocrine therapy resistance resulting in metastatic recurrence contributes to death of many breast cancer patients

Summary

Introduction

Estrogen (E2) binds and activates estrogen receptors (ERs) to enter the nucleus and regulate the expression of genes involved in cell survival, proliferation and differentiation [1]. ERαpositive breast cancers often acquire endocrine resistance and escape such therapy, likely through the activation of alternative mitotic pathways or ligand independent activation of ERα [2]. The phosphorylation of ERα at tyrosine 537 (Y537) is mediated by the c-Src (Src) kinase and promotes ERα hormone-binding, dimerization, and activity [3,4,5,6]. This phosphorylation is known to increase ERα association with Src to promote Src activation, as well as ERα extra-nuclear localization [5, 7, 8]

Methods

Results

Conclusion