CUL4A contributes to the biology of basal-like breast tumors through modulation of cell growth and antitumor immune response
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Laura P. Saucedo-Cuevas1, Isabel Ruppen2, Pilar Ximénez-Embún2, Samuel Domingo1, Javier Gayarre1,4, Javier Muñoz2, Jose M. Silva3, María J. García1,4, Javier Benítez1,4
1 Group of Human Genetics, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Spain
2 ProteoRed-ISCIII, Proteomics Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Spain
3 Institute for Cancer Genetics, Columbia University, New York, NY, USA
4 Spanish Network Research on Rare Diseases (CIBERER), Spain
Javier Benítez, email:
María J. García, email:
Keywords: CUL4A, 13q34 amplification, breast cancer, basal-like, proteomics, immune system
Received: March 04, 2014 Accepted: April 16, 2014 Published: April 18, 2014
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.
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