BCAS2 Enhances Carcinogenic Effects of Estrogen Receptor Alpha in Breast Cancer Cells.

Ángel Salmerón-Hernández,Albert Jordan,Elizabeth Langley,Noemi Baranda-Avila,María Noriega-Reyes

doi:10.3390/ijms20040966

Abstract

Estrogen receptor alpha (ERα) has an established role in breast cancer biology. Transcriptional activation by ERα is a multistep process modulated by coactivator and corepressor proteins. Breast Cancer Amplified Sequence 2 (BCAS2), is a poorly studied ERα coactivator. In this work, we characterize some of the mechanisms through which this protein increases ERα activity and how this promotes carcinogenic processes in breast cancer cells. Using protein-protein interaction and luciferase assays we show that BCAS2 interacts with ERα both in vitro and in vivo and upregulates transcriptional activation of ERα directly through its N-terminal region (AF-1) and indirectly through its C-terminal (AF-2) region, acting in concert with AF-2 interacting coactivators. Elevated expression of BCAS2 positively affects proliferation, clonogenicity and migration of breast cancer cells and directly activates ERα regulated genes which have been shown to play a role in tumor growth and progression. Finally, we used signal transduction pathway inhibitors to elucidate how BCAS2 is regulated in these cells and observed that BCAS2 is preferentially regulated by the PI3K/AKT signaling pathway. BCAS2 is an AF-1 coactivator of ERα whose overexpression promotes carcinogenic processes, suggesting an important role in the development of estrogen-receptor positive breast cancer.

Highlights

ERα is the primary therapeutic target in breast cancer and is expressed in close to 70% of cases
Using the yeast two-hybrid system to identify proteins that interact with the N-terminal domain of ERα, we obtained several sequences that encode for proteins that interact with this region, including Breast Cancer Amplified Sequence 2 (BCAS2)
We observed that BCAS2 interacts with full-length ERα, both in the presence and absence of E2 and that this interaction takes place via the N-terminal domain of ERα and not through its C-terminal domain, even in the presence of ligand (Figure 1B)

Summary

Introduction

ERα is the primary therapeutic target in breast cancer and is expressed in close to 70% of cases These tumors can respond to endocrine therapy and be growth inhibited by pharmacologic blockade of estrogen production or ER. Prolonged treatment often derives in endocrine resistance and tumor recurrence [1], through mechanisms which have not been completely elucidated Some of these mechanisms include ERα loss or mutations, changes in coregulatory proteins, increased cross-talk with other signal transduction pathways resulting in aberrant or ligand independent activation of ER or its coregulators and alternative downstream signaling pathways activating different gene expression programs [2,3,4,5,6]. Besides modulating chromatin structure to activate or repress transcription, coactivators and corepressors can have many other functions including control of splicing and protein degradation through ubiquitination. Expression of different coregulators has been implicated in differential tissue and cell type-specific responses to various hormones; more research is required to fully understand these mechanisms

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