Oncotarget

Research Papers:

GATA3 frameshift mutation promotes tumor growth in human luminal breast cancer cells and induces transcriptional changes seen in primary GATA3 mutant breast cancers

John P. Gustin, Jernelle Miller, Mina Farag, D. Marc Rosen, Matthew Thomas, Robert B. Scharpf and Josh Lauring _

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Oncotarget. 2017; 8:103415-103427. https://doi.org/10.18632/oncotarget.21910

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Abstract

John P. Gustin1, Jernelle Miller1, Mina Farag1, D. Marc Rosen1, Matthew Thomas1, Robert B. Scharpf1 and Josh Lauring1

1Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Correspondence to:

Josh Lauring, email: [email protected]

Keywords: GATA3, mutation, breast cancer, luminal

Received: October 05, 2017     Accepted: October 10, 2017     Published: October 20, 2017

ABSTRACT

The GATA3 transcription factor is one of the most frequently mutated genes in breast cancer. Heterozygous mutations, mostly frameshifts, are seen in 15% of estrogen receptor positive breast cancers, the subtype in which these mutations are almost exclusively found. Mouse studies have shown that Gata3 is critical for breast development and that GATA3 gene dosage affects breast tumor progression. Human patient data have shown that high Gata3 expression, a feature of luminal subtype breast cancers, is associated with a better prognosis. Although the frequency of GATA3 mutation suggests an important role in breast cancer development or progression, there is little understanding of how mutations in GATA3 affect its function in luminal breast epithelial cells and what gene expression changes result as a consequence of the mutations. Here, using gene editing, we have created two sets of isogenic human luminal breast cancer cell lines with and without a hotspot truncating GATA3 mutation. GATA3 mutation enhanced tumor growth in vivo but did not affect sensitivity to clinically used hormonal therapies or chemotherapeutic agents. We identified genes with upregulated and downregulated expression in GATA3 mutant cells, a subset of which was concordantly differentially expressed in GATA3 mutant primary luminal breast cancers. Addback of mutant GATA3 recapitulated mutation-specific gene expression changes and enhanced soft agar colony formation, suggesting a gain of function for the mutant protein.


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