Abstract
GATA3 is known to be one of the most frequently mutated genes in breast cancer. More than 10% of breast tumors carry mutations in this gene. However, the functional consequence of GATA3 mutations is still largely unknown. Clinical data suggest that different types of GATA3 mutations may have distinct roles in breast cancer characterization. In this study, we have established three luminal breast cancer cell lines that stably express different truncation mutants (X308 splice site deletion, C321 frameshift, and A333 frameshift mutants) found in breast cancer patients. Transcriptome analysis identified common and distinct gene expression patterns in these GATA3 mutant cell lines. In particular, the impacts on epithelial-to-mesenchymal transition (EMT) related genes are similar across these mutant cell lines. Chromatin localization of the mutants is highly overlapped and exhibits non-canonical motif enrichment. Interestingly, the A333 frameshift mutant expressed cells displayed the most significant impact on the GATA3 binding compared to X308 splice site deletion and C321fs mutants expressed cells. Our results suggest the common and different roles of GATA3 truncation mutations during luminal breast cancer development.
Highlights
Breast cancer is the most common cancer among women in the U.S and the second leading cause of cancer-related deaths
All GATA3 mutant cell lines exhibited synonymous wild-type GATA3 expression levels compared to the control cell line (Supplementary Figure 1B)
The cell number of the C321 frameshift mutant (C321fs) expressed cells on Day 5 was slightly higher, overall, the stable expression of these GATA3 truncation mutants did not exhibit a significant impact on T47D cell growth (Figure 1C)
Summary
Breast cancer is the most common cancer among women in the U.S and the second leading cause of cancer-related deaths. GATA3 is a reliable biomarker for breast carcinomas and is frequently used to determine the tissue of origin to confirm a diagnosis (Jensen et al, 2002; GarciaClosas et al, 2007; Bertucci et al, 1999; Liu et al, 2016; Hoch et al, 1999; Mehra et al, 2005; Sørlie et al, 2003; Chou et al, 2010; Takaku et al, 2015). Recent large-scale molecular profiling of breast carcinomas identified frequent mutations in GATA3 (Usary et al, 2004; The Cancer Genome Atlas Network, 2012). It has been shown that the cooperative action
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