The Role of EZH2 in Genomic Stability and Tumorigenesis in Breast Cancer

Honors (Bachelor's)BiochemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/79483/1/mduprie.pd

Improving Software Citation and Credit

The past year has seen movement on several fronts for improving software citation, including the Center for Open Science's Transparency and Openness Promotion (TOP) Guidelines, the Software Publishing Special Interest Group that was started at January's AAS meeting in Seattle at the request of that organization's Working Group on Astronomical Software, a Sloan-sponsored meeting at GitHub in San Francisco to begin work on a cohesive research software citation-enabling platform, the work of Force11 to "transform and improve" research communication, and WSSSPE's ongoing efforts that include software publication, citation, credit, and sustainability. Brief reports on these efforts were shared at the BoF, after which participants discussed ideas for improving software citation, generating a list of recommendations to the community of software authors, journal publishers, ADS, and research authors. The discussion, recommendations, and feedback will help form recommendations for software citation to those publishers represented in the Software Publishing Special Interest Group and the broader community.Comment: Birds of a Feather session organized by the Astrophysics Source Code Library (ASCL, http://ascl.net/ ); to be published in Proceedings of ADASS XXV (Sydney, Australia; October, 2015). 4 page

Histone Methyltransferase EZH2 Induces Akt-Dependent Genomic Instability and BRCA1 Inhibition in Breast Cancer

Increased levels of EZH2, a critical regulator of cellular memory, signal the presence of metastasis and poor outcome in breast cancer patients. High levels of EZH2 are associated with nuclear pleomorphism, lack of estrogen receptor expression, and decreased nuclear levels of BRCA1 tumor suppressor protein in invasive breast carcinomas. The mechanism by which EZH2 overexpression promotes the growth of poorly differentiated invasive carcinomas remains to be defined. Here, we show that EZH2 controls the intracellular localization of BRCA1 protein. Conditional doxycycline-induced upregulation of EZH2 in benign mammary epithelial cells results in nuclear export of BRCA1 protein, aberrant mitoses with extra centrosomes, and genomic instability. EZH2 inhibition in CAL51 breast cancer cells induces BRCA1 nuclear localization and rescues defects in ploidy and mitosis. Mechanistically, EZH2 overexpression is sufficient for activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway specifically through activation of Akt isoform 1. EZH2-induced BRCA1 nuclear export, aneuploidy, and mitotic defects were prevented by treatment with the PI3K inhibitors LY294002 or wortmannin. Targeted inhibition of Akt-1, Akt-2, and Akt-3 isoforms revealed that the EZH2-induced phenotype requires specific activation of Akt-1. The relevance of our studies to human breast cancer is highlighted by the finding that high EZH2 protein levels are associated with upregulated expression of phospho-Akt-1 (Ser473) and decreased nuclear expression of phospho-BRCA1 (Ser1423) in 39% of invasive breast carcinomas. These results enable us to pinpoint one mechanism by which EZH2 regulates BRCA1 expression and genomic stability mediated by the PI3K/Akt-1 pathway.Fil: Gonzalez, Maria E.. University of Michigan; Estados UnidosFil: DuPrie, Matthew L.. University of Michigan; Estados UnidosFil: Krueger, Heather. University of Michigan; Estados UnidosFil: Merajver, Sofia D.. University of Michigan; Estados UnidosFil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Toy, Kathy A.. University of Michigan; Estados UnidosFil: Kleer, Celina G.. University of Michigan; Estados Unido