MCF10A cells expressing GATA3 mutants

Patterns of somatic mutations in cancer genes provide information about their functional role in tumourigenesis and thus indicate their potential for therapeutic exploitation. Yet, the classical distinction between oncogene and tumour suppressor may not always apply. For instance, TP53 has been simultaneously associated with tumour suppressing and promoting activities. Here, we uncover a similar phenomenon for GATA3, a frequently mutated, yet poorly understood breast cancer gene. Surprisingly, we identify two functional classes of frameshift mutations that are associated with distinct expression profiles in tumours, differential disease-free patient survival and gain- and loss-of-function activities in a cell line model. We performed RNA sequencing on MCF10A cells expressing wild-type and two different GATA3 mutants (GATA3-wt, GATA3-ext, GATA3-trunc) or control vector expressing cells to characterise the effects of GATA3 mutations at the cellular level. These data indicated that expression of GATA3-ext and GATA3-trunc invoke starkly distinct changes in gene expression and the large number of uniquely regulated genes in GATA3-ext expressing cells supports a gain-of-function of this mutant.