Overstepping Boundaries: Hotspot Mutation in GATA3 Promotes EMT and Metastasis in Breast Cancer

Abstract

GATA3, a critical transcription factor in mammary gland development, has traditionally been regarded as a tumor suppressor in breast cancer. Mutations in GATA3, which are commonly believed to function through the elimination of these tumor suppressive effects, occur in over 10% of all breast cancer patients. This study aims to characterize a previously unexplored hotspot mutation that contributes to one-fifth of all GATA3 mutations.

Strikingly, rather than a loss of function, we find that this mutation produces a truncated, mutant GATA3 protein that confers an oncogenic gain of function. In cells, we observe that mutant GATA3 promotes migration and invasion, as well as epithelial-mesenchymal transition (EMT), which are characteristics that have been linked to increased metastatic potential in tumor cells. Consistent with these findings, we show that the mutant GATA3 promotes lung metastasis in several mouse models. A closer look at the primary tumors in these mice reveals a disorganization of tumor boundaries, presumably wrought by the invasion of tumor cells into surrounding tissues. We also gain valuable insight into mutant GATA3’s mechanisms by identifying its protein interactions, as well as direct downstream gene targets.

Taken together, these findings suggest that mutant GATA3 may serve as an early prognostic marker for breast cancer and provide a potential therapeutic target. These tools are relevant towards addressing the rising breast cancer epidemic in a number of countries, which we discuss in the context of the urban-rural fabric of India. This work is an exciting step forward towards promoting the health and dignity of breast cancer patients globally.