ABSTRACT
The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor clinical outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF7 cell line modified the effects of TGFß on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer.
Subject(s)
Breast Neoplasms/pathology , Carrier Proteins/metabolism , Mammary Glands, Human/cytology , Mammary Glands, Human/metabolism , Oncogene Proteins/metabolism , Animals , Cell Line , Cell Proliferation , Epithelial Cells , Female , Fibroblasts , Gene Expression Profiling , Humans , MiceABSTRACT
The Saccharomyces cerevisiae p21-activated kinase (PAK) Ste20 regulates various aspects of cell polarity during vegetative growth, mating and filamentous growth. To gain further insight into the mechanisms of Ste20 action, we screened for interactors of Ste20 using the split-ubiquitin system. Among the identified proteins were Erg4, Cbr1 and Ncp1, which are all involved in sterol biosynthesis. The interaction between Ste20 and Erg4, as well as between Ste20 and Cbr1, was confirmed by pull-down experiments. Deletion of either ERG4 or NCP1 resulted in various polarity defects, indicating a role for these proteins in bud site selection, apical bud growth, cell wall assembly, mating and invasive growth. Interestingly, Erg4 was required for the polarized localization of Ste20 during mating. Lack of CBR1 produced no detectable phenotype, whereas the deletion of CBR1 in the absence of NCP1 was lethal. Using a conditional lethal mutant we demonstrate that both proteins have overlapping functions in bud morphology.