14-3-3τ drives estrogen receptor loss via ERα36 induction and GATA3 inhibition in breast cancer

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.

Arnicolide C Suppresses Tumor Progression by Targeting 14-3-3θ in Breast Cancer

“…Compared with its expression in healthy tissues, 14-3-3θ is overexpressed in breast cancer tissues and plays a vital role in the metastasis and prognosis of breast cancer [ 45 ]. 14-3-3θ inhibition can affect the proliferation and metastasis of breast cancer cells via a mechanism related to inactivation of the Rapidly accelerated fibrosarcoma/extracellular regulated protein kinases (RAF/ERK), PI3K/AKT, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways [ 46 , 47 , 48 ]. Since 14-3-3θ plays an important role in the proliferation of cancer cells, new therapies targeting this protein have attracted increased amounts of attention.…”

Super-enhanced MARCO variant drives triple-negative breast cancer progression

“…Unfortunately, cancer cells have evolved to highjack the usage of alternative promoters for their own gains ( 3 ). Notable examples include an alternative transcription initiation (ATI) isoform of anaplastic lymphoma kinase ALK ATI in melanoma ( 4 ), an estrogen receptor isoform ERα36 in breast cancer ( 5 , 6 ), and multiple isoforms of p53 family proteins in a wide variety of cancers ( 7 ), to name a few. Identification of new oncogenic protein isoforms in each type of cancer will certainly enhance our understanding of cancer development and more importantly provide new opportunities for therapy.…”