ERβ alters the chemosensitivity of luminal breast cancer cells by regulating p53 function.

Igor Bado,Jan-Åke Gustafsson,Eric Pham,Benjamin Soibam,Fotis Nikolos,Christoforos Thomas

doi:10.18632/oncotarget.25147

Abstract

Estrogen receptor α (ERα)-positive breast cancers tend to develop resistance to both endocrine therapy and chemotherapy. Despite recent progress in defining molecular pathways that confer endocrine resistance, the mechanisms that regulate chemotherapy response in luminal tumors remain largely elusive. Luminal tumors often express wild-type p53 that is a major determinant of the cellular DNA damage response. Similar to p53, the second ER subtype, ERβ, has been reported to inhibit breast tumorigenesis by acting alone or in collaboration with p53. However, a synergistic mechanism of action has not been described. Here, we suggest that ERβ relies on p53 to elicit its tumor repressive actions in ERα-positive breast cancer cells. Upregulation of ERβ and treatment with ERβ agonists potentiates the tumor suppressor function of p53 resulting in decreased survival. This effect requires molecular interaction between the two proteins that disrupts the inhibitory action of ERα on p53 leading to increased transcriptional activity of p53. In addition, we show that the same interaction alters the chemosensitivity of endocrine-resistant cells including their response to tamoxifen therapy. Our results suggest a collaboration of ERβ and p53 tumor suppressor activity in breast cancer cells that indicates the importance of ligand-regulated ERβ as a tool to target p53 activity and improve the clinical management of resistant disease.

Highlights

70% of diagnosed breast cancers belong to estrogen receptor alpha (ERα)-positive phenotype [1, 2]
To test whether such synergism impacts the clinical outcome of patients with breast cancer, we tested the correlation between the combined expression of ERβ and p53 and relapse free survival in published Kaplan Meier (KM) plotter datasets and found that ERβhigh/p53high patients have better prognosis than ERβlow/p53low patients in Estrogen receptor α (ERα)-positive breast cancer cohort (Supplementary Figure 1A)
To investigate whether ERβ relies on such synergism to exert its repressive actions in breast cancer, we analyzed breast cancer cells that carry wild-type p53 for expression of p53-regulated genes that are involved in cell-cycle arrest, apoptosis, and senescence including p21, GADD45A, p53 upregulated modulator of apoptosis (PUMA), plasminogen activator inhibitor-1 (PAI-1), BAX, and promyelocytic leukemia protein (PML)

Summary

Introduction

70% of diagnosed breast cancers belong to estrogen receptor alpha (ERα)-positive phenotype [1, 2]. Part of the mechanism that links estrogen signaling to therapy resistance has been elucidated including the altered expression and/or post-translational modification of ERα that results in aberrant activity [5]. The discovery of ERβ indicated the complexity of estrogen signaling and suggested the possibility of the second ER to interfere with the pathways that contribute to resistant phenotypes. Both ERα and ERβ are transcription factors that regulate a plethora of genes by acting on estrogen-responseelements (ERE) or by interacting with other transcription factors [5, 6]. Despite similarities in the structure and the mechanism of action, the two ER subtypes elicit distinct transcriptional responses and differentially affect cancer www.oncotarget.com cellular processes which may imply separate roles in therapy resistance

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