Abstract
The CUL4A E3 ubiquitin ligase is involved in the regulation of many cellular processes and its amplification and/or overexpression has been observed in breast cancer. The 13q34 amplification, which is associated with the basal-like breast cancer subtype, has been proposed as one of the mechanism behind CUL4A up-regulation. However, the specific contribution of CUL4A to the biology of basal-like breast tumors has not yet been elucidated. In this work, by using cellular models of basal phenotype, we show the inhibitory effect of CUL4A silencing in the proliferation and growth of breast cancer cells both, in vitro and in vivo. We also demonstrate the transforming capacity of CUL4A exogenous overexpression in the 184B5 human mammary epithelial cells in vitro. Our results suggest a synergistic effect between CUL4A high levels and the activation of the RAS pathway in the tumorigenesis of basal-like breast cancer tumors. In addition, by using a proteomics approach we have defined novel candidate proteins and pathways that might mediate the oncogenic effect of CUL4A. In particular, we report a putative role of CUL4A in bypassing the immune system in breast cancer through the down-regulation of several molecules involved in the immune surveillance. These findings provide insight into the oncogenic properties of CUL4A in basal-like breast cancer and highlight the therapeutic opportunities to target CUL4A.
Highlights
The CUL4A E3 ubiquitin ligase belongs to the family of cullin proteins and is a component of the cullin-RING ligase 4A complex [1]
We examined the expression of CUL4A in 11 human breast cancer cell lines and two non-transformed human mammary epithelial cell lines by quantitative PCR and Western blot (WB)
One of the mechanisms triggering CUL4A overexpression is the 13q34 amplification and this genomic aberration has been shown to be associated with breast tumors characterized by exhibiting BRCA1 impairment or a basal-like phenotype [12, 13]
Summary
The CUL4A E3 ubiquitin ligase belongs to the family of cullin proteins and is a component of the cullin-RING ligase 4A complex [1]. This complex plays a crucial role in the regulation of both stability and degradation of a huge spectrum of cellular proteins through the ubiquitin-proteasome system [1, 2]. A recent functional analysis of CUL4A has revealed a pivotal role of the gene www.impactjournals.com/oncotarget in regulating the metastatic behavior of breast cancer cells [11]
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