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Mol Cell Endocrinol. 2020 Mar 1;503:110693. doi: 10.1016/j.mce.2019.110693. Epub 2019 Dec 24.

Identification of a novel C-terminally truncated estrogen receptor α variant (ERαi34) with constitutive transactivation and estrogen receptor antagonist resistance.

Author information

1
Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan. Electronic address: hirotaka@nms.ac.jp.
2
Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan. Electronic address: yujiro@nms.ac.jp.
3
Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan. Electronic address: hozawa@nms.ac.jp.

Abstract

Constitutively active estrogen receptor α (ERα) variants with C-terminal truncation are candidate molecules for gain of both endocrine- and chemotherapy-resistance in estrogen-sensitive tumors. Our previous reports using artificially truncated ERα constructs demonstrated that ERα variants encoded in 1-2-3-cryptic exon- and 1-2-3-4-cryptic exon-types of transcripts have potentials to display constitutive transactivation of an estrogen response element reporter. However, naturally occurring 1-2-3-cryptic exon-type ERα variants have not been cloned yet. Therefore, the present study was designed to identify naturally occurring ERα variants encoded in 1-2-3-cryptic exon-type ERα transcripts. We cloned a novel C-terminally truncated ERα variant (ERαi34) encoded in a 1-2-3-i34 transcript from MCF-7 cells and characterized its constitutive and ER antagonist-resistant transactivation in transfected cells. Stable transfection of the variant into MCF-7 cells augmented basal cell proliferation insensitive to fulvestrant. Collectively, we validated the structure-based mechanisms underlying constitutive and ER antagonist-resistant transactivation by C-terminally truncated ERα variants.

KEYWORDS:

Alternative splicing; Chemotherapy resistance; ESR1; Endocrine resistance; Splice variant

PMID:
31881246
DOI:
10.1016/j.mce.2019.110693

Conflict of interest statement

Declaration of competing interest The authors declare that they do not have any conflicts of interest to disclose.

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