GATA3 Truncating Mutations Promote Cistromic Re-Programming In Vitro, but Not Mammary Tumor Formation in Mice
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Heterozygous mutations in the transcription factor GATA3 are identified in 10–15% of all breast cancer cases. Most of these are protein-truncating mutations, concentrated within or downstream of the second GATA-type zinc-finger domain. Here, we investigated the functional consequences of expression of two truncated GATA3 mutants, in vitro in breast cancer cell lines and in vivo in the mouse mammary gland. We found that the truncated GATA3 mutants display altered DNA binding activity caused by preferred tethering through FOXA1. In addition, expression of the truncated GATA3 mutants reduces E-cadherin expression and promotes anchorage-independent growth in vitro. However, we could not identify any effects of truncated GATA3 expression on mammary gland development or mammary tumor formation in mice. Together, our results demonstrate that both truncated GATA3 mutants promote cistromic re-programming of GATA3 in vitro, but these mutants are not sufficient to induce tumor formation in mice.
KeywordsGATA3 Breast cancer Truncating mutations Cistromic re-programming
We are grateful to Anne Paulien Drenth, Eline van der Burg and Eva Schut for their technical support with the animal studies. We thank the Netherlands Cancer Institute Genomics Core Facility, Mouse Clinic for Cancer and Aging, Animal Facility, and Animal Pathology Facility for their expert technical support.
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Statement of Author Contributions
LMC, WZ and JJ designed research. LMC and LH performed research. LMC, RB, YK, WZ and JJ analyzed data. LMC, WZ and JJ wrote the paper.
This work was financially supported by the Oncode Institute; the Center for Translational Molecular Medicine (CTMM) Breast Care Project; the Netherlands Organization for Scientific Research (NWO: Cancer Genomics Netherlands (CGCNL), Cancer Systems Biology Center (CSBC), Zenith 93512009, Vici 91814643); the EU Seventh Framework Program (EurocanPlatform project 260791); the European Research Council (ERC Synergy project CombatCancer); and a National Roadmap grant for Large-Scale Research facilities from NWO.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that there are no conflicts of interest
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