IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
artículos
Título:
Histone Methyltransferase EZH2 Induces Akt-Dependent Genomic Instability and BRCA1 Inhibition in Breast Cancer
Autor/es:
ME GONZALEZ; ML DUPRIE; H KRUEGER ; SD MERAJVER ; ALEJANDRA C VENTURA; KA TOY; CG KLEER
Revista:
CANCER RESEARCH
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Año: 2011 vol. 71 p. 2360 - 2370
ISSN:
0008-5472
Resumen:
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.