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2.  CUL4A contributes to the biology of basal-like breast tumors through modulation of cell growth and antitumor immune response 
Oncotarget  2014;5(8):2330-2343.
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.
PMCID: PMC4039166  PMID: 24870930
CUL4A; 13q34 amplification; breast cancer; basal-like; proteomics; immune system
4.  Profiling Essential Genes in Human Mammary Cells by Multiplex RNAi Screening 
Science (New York, N.Y.)  2008;319(5863):617-620.
By virtue of their accumulated genetic alterations, tumor cells may acquire vulnerabilities that create opportunities for therapeutic intervention. We have devised a massively parallel strategy for screening short hairpin RNA (shRNA) collections for stable loss-of-function phenotypes. We assayed from 6000 to 20,000 shRNAs simultaneously to identify genes important for the proliferation and survival of five cell lines derived from human mammary tissue. Lethal shRNAs common to these cell lines targeted many known cell-cycle regulatory networks. Cell line–specific sensitivities to suppression of protein complexes and biological pathways also emerged, and these could be validated by RNA interference (RNAi) and pharmacologically. These studies establish a practical platform for genome-scale screening of complex phenotypes in mammalian cells and demonstrate that RNAi can be used to expose genotype-specific sensitivities.
PMCID: PMC2981861  PMID: 18239125
5.  Gliding Resistance and Strength of a Braided Polyester/Monofilament Polyethylene Composite (FiberWire®) Suture in Human Flexor Digitorum Profundus Tendon Repair: An In-Vitro Biomechanical Study 
The Journal of hand surgery  2009;34(1):87-92.
While the strength of a tendon repair is clearly important, the friction of the repair is also a relevant consideration. The purpose of this study was to characterize the frictional coefficient, gliding resistance and breaking strength of suture materials and a suture construct commonly used for flexor tendon repair.
We measured the friction coefficients of 3-0 braided nylon enclosed in a smooth nylon outer shell (Supramid, S. Jackson, Alexandria, VA), 3-0 braided polyester coated with polybutilate (Ethibond, Ethicon, Somerville, NJ), and a 3-0 braided polyester/monofilament polyethylene composite (FiberWire, Arthrex, Naples, FL) sutures. We also measured the gliding resistance, linear breaking strength and resistance to gapping of zone 2 modified Pennington tendon repairs with the two lowest friction sutures in 20 human cadaveric flexor digitorum profundus (FDP) tendons.
The braided polyester/monofilament polyethylene composite had a significantly lower friction coefficient (0.054) than either the coated polyester (0.076) or nylon (0.130) sutures (p<0.001). The gliding resistances of the repaired tendons with braided/monofilament polyethylene composite suture and coated, braided polyester were similar (p> 0.05). The strength of the two repairs, force to produce a 2mm gap, and resistance to gap formation than coated, braided polyester repairs were also not significantly different.
Braided polyester composite is a low friction suture material. However, when this suture was used for tendon repair with a locking suture technique, it did not show a significant effect on the gliding resistance and repair strength compared with the same repair using coated polyester suture.
PMCID: PMC2796445  PMID: 19121735
Gliding Resistance; Suture; Tendon; Tendon Repair
6.  Cyfip1 is a putative invasion suppressor in epithelial cancers 
Cell  2009;137(6):1047-1061.
Identification of bona fide tumor suppressors is often challenging because of the large number of alterations present in most human cancers. To evaluate candidates present within regions recurrently deleted in human cancers we coupled high-resolution genomic analysis with a two-stage genetic study using RNA interference (RNAi). We found that Cyfip1, a subunit of the WAVE complex, which regulates cytoskeletal dynamics, is commonly deleted in human epithelial cancers. Reduced expression of Cyfip1 is commonly observed during invasion of epithelial tumors and it associated with poor prognosis in same tumor types. Silencing of Cyfip1 disturbed normal epithelial morphogenesis in vitro and cooperated with oncogenic Ras to produce invasive carcinomas in vivo. Mechanistically, we have linked alterations in WAVE-regulated actin dynamics with impaired cell-cell adhesion and cell-ECM interactions. Thus, we propose Cyfip1 as an invasion suppressor gene.
PMCID: PMC2754270  PMID: 19524508

Results 1-6 (6)