SWI/SNF chromatin remodeling complexes regulate critical cellular processes including cell cycle control, programmed cell death, differentiation, genomic instability and DNA repair. Inactivation of this class of chromatin remodeling complex has been associated with a variety of malignancies, including lung, ovarian, renal, liver and pediatric cancers. In particular, ~10% of primary human lung non-small lung cancers (NSCLC) display attenuations in the BRG1 ATPase, a core factor in SWI/SNF complexes. To evaluate the role of BRG1 attenuation in NSCLC development, we examined the effect of BRG1 silencing in primary and established human NSCLC cells. BRG1 loss altered cellular morphology and increased tumorigenic potential. Gene expression analyses showed reduced expression of genes known to be associated with progression of human NSCLC. We demonstrated that BRG1 losses in NSCLC cells were associated with variations in chromatin structure, including differences in nucleosome
positioning and occupancy surrounding transcriptional start sites of disease-relevant genes. Our results offer direct evidence that BRG1 attenuation contributes to NSCLC aggressiveness by altering nucleosome positioning at a wide range of genes, including key cancer-associated genes.

One of the earliest events in epithelial carcinogenesis is the dissolution of tight junctions and cell polarity signals that are essential for normal epithelial barrier function. Here, we report that EFA6B, a guanine nucleotide exchange factor for the Ras superfamily protein Arf6 that helps assemble and stabilize tight junction, is required to maintain apico-basal cell polarity and mesenchymal phenotypes in mammary epithelial cells. In organotypic three-dimensional cell cultures, endogenous levels of EFA6B were critical to determine epithelial–mesenchymal status. EFA6B downregulation correlated with a mesenchymal phenotype and ectopic expression of EFA6B hampered TGFβ-induced epithelial-to-mesenchymal transition (EMT). Transcriptomic and immunohistochemical analyses of human breast tumors revealed that the reduced expression of EFA6B was associated with loss of tight junction components and with increased signatures of EMT, cancer stemness, and poor prognosis. Accordingly, tumors with low levels of EFA6B were enriched in the aggressive triple-negative and claudin-low breast cancer subtypes. Our results identify EFA6B as a novel antagonist in breast cancer and they point to its regulatory and signaling pathways as rational therapeutic targets in aggressive forms of this disease. Cancer Res; 74(19); 1–14. ©2014 AACR.

At Penn Medicine, we don’t just treat cancer, we treat your cancer.

If you need radiation treatment, rest assured—you’ll get the same great Penn doctors, the same Penn evaluation team and the same outstanding care, at every one of our eight Philadelphia area locations. And each location has access to the latest in radiation technology, advanced treatment options and clinical trials. Some treatment options, like proton therapy, are only found here.

Our teams work with you to create the most personalized treatment plan, based on where you live, how you live and most importantly, the type of treatment you need.

This belief, this commitment, that your treatment should be as unique as you are, has made the Abramson Cancer Center the region’s #1 cancer program.

Penn Medicine Radiation Oncology Locations

• Penn Radiation Oncology Chester County Hospital
• Penn Radiation Oncology Chestnut Hill
• Penn Radiation Oncology Doylestown
• Penn Radiation Oncology Kennett Square
• Penn Radiation Oncology Pennsylvania Hospital (Center City)
• Penn Radiation Oncology Perelman Center for Advanced Medicine (University City)
• Penn Radiation Oncology Radnor
• Penn Radiation Oncology Valley Forge

Mutations in the APC or β-catenin genes are well-established initiators of colorectal cancer, yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacologic approaches in mouse colorectal cancer and human colorectal cancer xenograft models, we show that incipient intestinal tumor cells activate CDC42, an APC-interacting small GTPase, as a crucial step in malignant progression. In the mouse, Cdc42 ablation attenuated the tumorigenicity of mutant intestinal cells carrying single APC or β-catenin mutations. Similarly, human colorectal cancer with relatively higher levels of CDC42 activity was particularly sensitive to CDC42 blockade. Mechanistic studies suggested that Cdc42 may be activated at different levels, including at the level of transcriptional activation of the stem cell–enriched Rho family exchange factor Arhgef4. Our results indicate that early-stage mutant intestinal epithelial cells must recruit the pleiotropic functions of Cdc42 for malignant progression, suggesting its relevance as a biomarker and therapeutic target for selective colorectal cancer intervention. Cancer Res; 74(19); 1–13. ©2014 AACR.

Taking small amounts of aspirin over long periods of time reduces the risk of colon cancer and certain other cancers.