Shift in GATA3 functions, and GATA3 mutations, control progression and clinical presentation in breast cancer

Helit Cohen, Rotem Ben-Hamo, Moriah Gidoni, Ilana Yitzhaki, Renana Kozol, Alona Zilberberg, Sol Efroni

IntroductionGATA3 is a regulator of mammary luminal cell differentiation, and an estrogen receptor (ER) associated marker in breast cancer. Tumor suppressor functions of GATA3 have been demonstrated primarily in basal-like breast cancers. Here, we focused on its function in luminal breast cancer, where GATA3 is frequently mutated, and its levels are significantly elevated.MethodsGATA3 target genes were identified in normal- and luminal cancer- mammary cells by ChIP-seq, followed by examination of the effects of GATA3 expressions and mutations on tumorigenesis-associated genes and processes. Additionally, mutations and expression data of luminal breast cancer patients from The Cancer Genome Atlas were analyzed to characterize genetic signatures associated with GATA3 mutations.ResultsWe show that some GATA3 effects shift from tumor suppressing- to tumor promoting during tumorigenesis, with deregulation of three genes, BCL2, DACH1, THSD4, representing major GATA3-controlled processes in cancer progression. In addition, we identify an altered activity of mutant GATA3, and distinct associated genetic signatures. These signatures depend on the functional domain mutated; and, for a specific subgroup, are shared with basal-like breast cancer patients, who are a clinical group with regard to considerations of mode of treatment.ConclusionThe GATA3 dependent mechanisms may call for special considerations for proper prognosis and treatment of patients.