Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets

Oncogene. 2018 Aug;37(33):4581-4598. doi: 10.1038/s41388-018-0284-2.

Leah A Gates ¹ ², Guowei Gu ¹ ³, Yue Chen ⁴, Aarti D Rohira ¹, Jonathan T Lei ³ ⁵, Ross A Hamilton ¹, Yang Yu ¹, David M Lonard ¹, Jin Wang ¹ ⁶ ⁷, Shu-Ping Wang ⁸, David G Edwards ³, Philip F Lavere ¹, Jiangyong Shao ¹, Ping Yi ¹, Antrix Jain ¹, Sung Yun Jung ⁹, Anna Malovannaya ¹ ⁹, Shunqiang Li ¹⁰, Jieya Shao ¹⁰, Robert G Roeder ⁸, Matthew J Ellis ³ ⁵ ¹¹, Jun Qin ¹ ⁹, Suzanne A W Fuqua ³ ¹¹, Bert W O'Malley ¹ ¹¹, Charles E Foulds ¹² ¹³

Affiliations

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
2 Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, 10065, USA.
3 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA.
4 Employee of Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130, USA.
5 Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
6 Department of Pharmacology, Baylor College of Medicine, Houston, TX, 77030, USA.
7 Center for Drug Discovery, Baylor College of Medicine, Houston, TX, 77030, USA.
8 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, 10065, USA.
9 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
10 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
11 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
12 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. foulds@bcm.edu.
13 Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030, USA. foulds@bcm.edu.

PMID: 29748621 DOI: 10.1038/s41388-018-0284-2

Abstract

Approximately 75% of breast cancers are Estrogen Receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10-40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERα proteins may offer new therapeutic targets for endocrine-resistant Cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ERα LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ERα. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast Cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-12870

AZD9496

99.40%, ERα Antagonist

Estrogen Receptor/ERR

Cancer

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