14-3-3τ Drives Estrogen Receptor Loss via ERα36 Induction and GATA3 Inhibition in Breast Cancer

Authors

Lidija A Wilhelms Garan
Yang Xiao
Weei-Chin Lin

Publication Date

10-25-2022

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2209211119

PMID

36252018

PMCID

PMC9618134

PubMedCentral® Posted Date

10-17-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Female, Humans, Breast Neoplasms, Cell Line, Tumor, Estrogen Receptor alpha, GATA3 Transcription Factor, Gene Expression Regulation, Neoplastic, Protein Isoforms, Proto-Oncogene Proteins c-akt, Tamoxifen, 14-3-3 Proteins, 14-3-3τ, estrogen receptor, ERα36, GATA3, 3D tumor spheroid model

Abstract

About one-fourth of recurrent estrogen receptor-positive (ER+) breast cancers lose ER expression, leading to endocrine therapy failure. However, the mechanisms underlying ER loss remain to be fully explored. We now show that 14-3-3τ, up-regulated in ∼60% of breast cancer, drives the conversion of ER+ to ER- and epithelial-to-mesenchymal transition (EMT). We identify ERα36, an isoform of ERα66, as a downstream effector of 14-3-3τ. Overexpression of 14-3-3τ induces ERα36 in xenografts and tumor spheroids. The regulation is further supported by a positive correlation between ERα36 and 14-3-3τ expression in human breast cancers. ERα36 can antagonize ERα66 and inhibit ERα66 expression. Isoform-specific depletion of ERα36 blocks the ER conversion and EMT induced by 14-3-3τ overexpression in tumor spheroids, thus establishing ERα36 as a key mediator in 14-3-3τ-driven ER loss and EMT. ERα36 promoter is repressed by GATA3, which can be phosphorylated by AKT at consensus binding sites for 14-3-3. Upon AKT activation, 14-3-3τ binds phosphorylated GATA3 and facilitates the degradation of GATA3 causing GATA3 to lose transcriptional control over its target genes ERα66 and ERα36. We also demonstrate a role for the collaboration between 14-3-3τ and AKT in ERα36 induction and endocrine therapy resistance by three-dimensional spheroid and tamoxifen treatment models in MCF7 and T47D ER+ breast cancer cells. Thus, the 14-3-3τ-ERα36 regulation provides a previously unrecognized mechanism for ER loss and endocrine therapy failure.

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