The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

Abstract

As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which converge into a neoprotein that we called “neoGATA3,” associated with excellent prognosis in patients. Analysis of available molecular data from >3000 breast cancer patients revealed a dysregulation of the ER-dependent transcriptional response in tumors carrying neoGATA3-generating mutations. Mechanistic studies in vitro showed that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated that ER binding is reduced in neoGATA3-expressing cells, especially at distal regions, suggesting that neoGATA3 interferes with the fine tuning of ER-dependent gene expression. This has opposite outputs in distinct hormonal context, having pro- or anti-proliferative effects, depending on the estrogen/progesterone ratio. Our data call for functional analyses of putative cancer drivers to guide clinical application.

Genomic profiling reveals heterogeneous populations of ductal carcinoma in situ of the breast

“…GATA3 promotes differentiation of luminal cells and inhibits infiltration and metastasis of breast cancer cells 42 – 46 . GATA3 mutation, which occurs at a high incidence rate in IDC 47 , is believed to abolish this critical function and promote the progression of cells to a more advanced stage 48 . Therefore, GATA3 mutations may play critical roles in migration and invasion of cancer cells but not in initial carcinogenesis.…”

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

“…Mutation R330fs was on the other hand reported to alter genomic distribution of ERα and FOXA1, leading to changes in gene regulation affecting genes involved in mammary gland development and epithelial cell biology [ 170 ]. In contrast, the X308_splice mutation, which generates a GATA3 protein lacking the second zinc finger but containing a novel 44 aa C-terminal end, downregulates ER genomic signaling and is associated with improved overall survival in ER+ patients [ 171 ].…”

GATA3 Truncation Mutants Alter EMT Related Gene Expression via Partial Motif Recognition in Luminal Breast Cancer Cells

“…Two nucleotide (CA) deletion at the splice acceptor site induces alternative splicing by using a new splice acceptor site seven nucleotides downstream. This results in a frameshift and protein truncation due to the immature stop codon (Takaku et al, 2015;Hruschka et al, 2020). The protein product entirely loses the original (wild-type) amino acid sequence of the ZnFn2 DNA binding domain.…”

“…These distinct clinical features suggest the differential impacts of GATA3 mutations on breast cancer cells. However, the biological significance and consequences, including the cellular function of these mutants, are not well-studied (Usary et al, 2004;Gustin et al, 2017;Emmanuel et al, 2018;Takaku et al, 2018;Hruschka et al, 2020;Takaku et al, 2020). In this study, we have established three luminal breast cancer cell lines that stably express different GATA3 truncation mutants found in breast cancer.…”