ERβ1: characterization, prognosis, and evaluation of treatment strategies in ERα-positive and -negative breast cancer.

Jordan M Reese,Vivian Negron,Barbara A Pockaj,Matthew P Goetz,Heather E Cunliffe,Carol Reynolds,Wilma L Lingle,Sejal S Shah,Malayannan Subramaniam,John R Hawse,Thomas C Spelsberg,Xianglin Wu,Janet E Olson,Kevin S Pitel,Ann E Mccullough,Vera J Suman,Anne Gingery,Fergus J Couch,James N Ingle

doi:10.1186/1471-2407-14-749

Jordan M Reese, Vivian Negron + Show 17 more

Open Access

https://doi.org/10.1186/1471-2407-14-749

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Abstract

BackgroundThe role and clinical value of ERβ1 expression is controversial and recent data demonstrates that many ERβ antibodies are insensitive and/or non-specific. Therefore, we sought to comprehensively characterize ERβ1 expression across all sub-types of breast cancer using a validated antibody and determine the roles of this receptor in mediating response to multiple forms of endocrine therapy both in the presence and absence of ERα expression.MethodsNuclear and cytoplasmic expression patterns of ERβ1 were analyzed in three patient cohorts, including a retrospective analysis of a prospective adjuvant tamoxifen study and a triple negative breast cancer cohort. To investigate the utility of therapeutically targeting ERβ1, we generated multiple ERβ1 expressing cell model systems and determined their proliferative responses following anti-estrogenic or ERβ-specific agonist exposure.ResultsNuclear ERβ1 was shown to be expressed across all major sub-types of breast cancer, including 25% of triple negative breast cancers and 33% of ER-positive tumors, and was associated with significantly improved outcomes in ERα-positive tamoxifen-treated patients. In agreement with these observations, ERβ1 expression sensitized ERα-positive breast cancer cells to the anti-cancer effects of selective estrogen receptor modulators (SERMs). However, in the absence of ERα expression, ERβ-specific agonists potently inhibited cell proliferation rates while anti-estrogenic therapies were ineffective.ConclusionsUsing a validated antibody, we have confirmed that nuclear ERβ1 expression is commonly present in breast cancer and is prognostic in tamoxifen-treated patients. Using multiple breast cancer cell lines, ERβ appears to be a novel therapeutic target. However, the efficacy of SERMs and ERβ-specific agonists differ as a function of ERα expression.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-749) contains supplementary material, which is available to authorized users.

Highlights

The role and clinical value of ERβ1 expression is controversial and recent data demonstrates that many ERβ antibodies are insensitive and/or non-specific
Our results demonstrate that ERβ1 is expressed across all tumor sub-types, including triple negative breast cancers (TNBC), and is significantly associated with improved patient outcomes in women taking tamoxifen for adjuvant therapy of resected, ERα-positive, early stage breast cancer
We explored the utility of therapeutically targeting ERβ1 using ERβ-specific agonists and multiple anti-estrogenic compounds in both ERα-positive and ERα-negative breast cancers using a number of cell model systems

Summary

Introduction

The role and clinical value of ERβ1 expression is controversial and recent data demonstrates that many ERβ antibodies are insensitive and/or non-specific. A number of microarray studies from our laboratory and others have demonstrated that these two proteins function differently in response to both estrogen and anti-estrogens [8,9,10,11,12,13,14]. Consistent with these data, the genome wide chromatin binding profiles, or cistromes, of ERα and ERβ1 share only 40% overlap following short term estrogen treatment [14]

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