Highlights of This Issue

Abstract

Despite promising preclinical evidence, therapies targeting the insulin-like growth factor (IGF) fail for many Ewing sarcoma patients, suggesting the influence of additional cellular factors. Patel and colleagues performed a genomic analysis using FAIRE-seq, which unexpectedly revealed PTEN deletion and loss of PTEN expression in a large fraction of primary human tumors. PTEN deficiency was associated with hyperactivation of AKT signaling and a more aggressive cellular phenotype. Strikingly, PTEN loss decreased sensitivity to IGF1 receptor inhibitors but increased responsiveness to temsirolimus, an mTOR inhibitor, marked by increased autophagy and an associated decrease in viability. These data support PTEN status as a clinically relevant biomarker to guide patient treatment.Pediatric malignant rhabdoid tumors (MRT) generally arise from inactivation of SNF5 (SMARCB1/INI1), a subunit of the macromolecular SWI/SNF chromatin-remodeling complex. However, the mechanism by which SNF5 loss initiates MRT development remains unclear. Wei and colleagues used mass spectrometry-based proteomics to demonstrate that SNF5 loss in MRT alters the subunit composition of the SWI/SNF complex. Importantly, SNF5 restoration rescues SWI/SNF complex integrity. Therefore, SNF5 inactivation drives the appearance of MRTs by dramatically modifying the composition of SWI/SNF complexes and preventing formation of complexes required for cellular differentiation.As a synthetic lethality-based cancer therapeutic strategy, PARP inhibition selective for BRCA1/2 deficiency has shown promising effect; therefore, defining human tumors with wild-type BRCA1/2 genes that are also sensitive to PARP inhibitors is of great clinical interest. Liu and colleagues show that TGFβ, a multitasking cytokine elevated in tumor microenvironments, regulates DNA repair by simultaneously suppressing the gene expression of ATM, MSH2, and BRCA1, resulting in a “BRCAness” phenotype that includes impaired DNA repair efficiency and reduced genomic stability, as well as a synthetic lethality to PARP inhibition. This approach improves selection of breast cancer patients based on TGFβ pathway biomarkers for PARP-targeting therapy.Estrogen and its receptors, predominantly ERα, are important mediators and therapeutic targets in hormone-dependent breast cancer. Cellular and epidemiologic evidence indicates that the G protein-coupled estrogen receptor (GPR30/GPER) has tumorigenic potential. To directly determine the oncogenic role of GPER in breast tumorigenesis, Marjon and colleagues intercrossed GPER-null mice with mammary tumor–prone MMTV-PyMT transgenic mice. Mice lacking GPER displayed reduced tumors with lower mitotic index and histologic grade. Moreover, distant metastasis was greatly diminished in GPER-deficient mice. These findings reveal that GPER contributes to tumorigenesis and, importantly, to metastasis, suggesting GPER as a new diagnostic and therapeutic target in breast cancer.