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

Abstract

1As the catalogue of oncogenic driver mutations is expanding, it is becoming clear that alterations 2 in a given gene should not be lumped into one single class, since they might have different functions. The 3 transcription factor GATA3 is a paradigm of this. Here, we address the functions of the most common 4 GATA3 mutation (X308_Splice) which generates a neoprotein that we designate as neoGATA3, associated 5 with good patient prognosis. Based on extensive analyses of molecular and clinical data from 6 approximately 3000 breast cancer patients, supported by mechanistic studies in vitro, we show that 7 neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone 8 receptors, without fully abrogating them. This has opposite outputs in the pre-or post-menopausal 9 hormonal context, having pro-or anti-proliferative effects, respectively. NeoGATA3 is an example of a 10 context-and stage-dependent driver mutation. Our data call for functional analyses of putative cancer 11 drivers to guide clinical application. 12 13Several evidences indicate that GATA3 is involved in the activation of the mammary 1 differentiation program: 1) in normal tissue, it is necessary for the formation of the luminal compartment 2 [9]; 2) GATA3 expression in BC strongly correlates with estrogen receptor (ER) expression [10]; 3) GATA3 3 functions in a complex with FOXA1 and ER to recruit RNA polymerase and enhance transcription of ER-4 responsive genes [11]; and 4) ectopic expression in GATA3-negative basal-like BC cells is sufficient to 5 induce luminal differentiation and inhibit tumor dissemination [12]. Consistent with this function, GATA3 6 expression decreases during the progression to metastatic BC [13]. The high frequency of GATA3 7 mutations in BC supports the idea that they are driver mutations, but whether they result in loss-of-8 function (LOF) or gain-of-function (GOF) is not fully clear. Most GATA3 mutations are rare or unique 9 frameshift indels (insertion/deletions) distributed along the 3' end of the gene ( Figure 1A), consistent with 10

GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients

“…Wnt/β-catenin signaling pathway is a modulating factor of mammary gland morphogenesis and cell properties 20 and mediates the increase of GATA3 expression 21 . Consistent with our finding, a previous study indicated WNT/β-catenin signaling as an enriched gene set in GATA3 X308_Splice mutant breast tumor 35 . Cell adhesion molecules (CAMs) was another different gene set between tumor samples.…”

“…However, non-mutant samples showed better survival than others in ER-positive patients. METABRIC data indicated the prognostic value of GATA3 X308_Splice mutation, as the mutant samples had better survival than wild-type ones both in all patients and ER-positive patients 35 . On the other hand, in samples representing a high expression of GATA3 , mutant patients had longer survival than wild-types, and mutations in the second GATA3 zinc-finger (ZnFn2) was associated with lower survival time than other mutations 36 .…”

Emerging role of pioneer transcription factors in targeted ERα positive breast cancer

“…GATA3 binds to the chromatin and plays a the pioneering role in the recruitment of ERα and promotes the abnormal proliferation of cells as well as it strongly correlates with ER expression in BC malignancy [37]. GATA3 functions with FOXA1 and ER to enhance ER-responsive genes in normal and pathological situations [38]. Studies provide evidence of additional ERα-cooperating activity of GATA3, which can mediate with enhancer at ERα regulatory regions and has properties similar to FOXA1 [39,40].…”