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

Language

English

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

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.

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

Published Open-Access

yes

Recommended Citation

Lidija A Wilhelms Garan, Yang Xiao, and Weei-Chin Lin, "14-3-3τ Drives Estrogen Receptor Loss via ERα36 Induction and GATA3 Inhibition in Breast Cancer" (2022). Faculty and Staff Publications. 1596.
https://digitalcommons.library.tmc.edu/baylor_docs/1596