Yanagishita et al. Page 440

Espin (ESPN) is a multifunctional actin-bundling protein and is an important regulator of cytoskeleton dynamics. At present, there have been no reports showing the expression and function of Espin in cancers, including melanoma. Yanagishita and colleagues reveal that Espin is strongly expressed in human melanomas as well as in RET-transgenic mice. Moreover, depletion of Espin has a dramatic impact on the metastatic activity of melanoma cells in vitro and in vivo. These findings reveal Espin not only as a novel metastatic regulator in melanoma but also as a potential biomarker for disease progression.

Xu et al. Page 359

The p53 tumor suppressor family member, p63 (TP63), plays a pivotal role in epidermal development, aging, and tumorigenesis. In an effort to understand the underlying mechanism by which p63 expression is controlled, Xu and colleagues identify the RNA-binding protein RBM24 as a novel regulator of p63 status via mRNA stability. Specifically, overexpression of RBM24 decreases, whereas knockdown of RBM24 increases, p63 expression. Mechanistically, RBM24 is able to bind to multiple regions in the 3′UTR of p63 and destabilize the p63 transcript. Together, these observations provide significant insight into the understanding of how p63 expression is regulated through a posttranscriptional mechanism.

Lin et al. Page 381

Management of epithelial ovarian cancer (EOC) that harbors wild-type BRCA remains a major challenge due to acquired chemoresistance and poor overall survival. Development of mechanism-based and/or targeted combination therapy approaches is critically needed for improved clinical outcome. Lin and colleagues demonstrate that triapine, a small molecule inhibitor of ribonucleotide reductase, sensitizes BRCA wild-type EOC cells to PARP and topoisomerase II inhibitors. Mechanistic studies demonstrate that triapine impairs homologous recombination repair (HRR) by obliterating CtIP phosphorylation, DNA double-strand break (DSB) resection, BRCA1 and Rad51 foci formation, and endonuclease-induced DSB repair. These findings provide a strong rationale for targeting HRR and using triapine to augment the efficacy of PARP and topoisomerase inhibitors for the treatment of BRCA wild-type EOC.

Bailey et al. Page 408

HER2/Neu (ERBB2) is a tyrosine kinase and is a major contributor to disease progression in various types of breast cancer. Consequently, its biomarker status is fundamentally important and its activity is a key target for therapeutics. Despite initial efficacy, HER2-targeted treatment approaches eventually result in resistance. Here, Bailey and colleagues report that NF-κB activity renders HER2-positive cancers resistant to HER2-directed therapy. Interestingly, Lapatinib-resistant cells had altered NF-κB and were more sensitive to simultaneous HER2 and NF-κB inhibitor treatment than either therapy alone. Through the use of genomic analyses, a NF-κB signature was deduced that correlated with clinical outcome. Thus, this study implicates NF-κB in HER2 therapy resistance and suggests that combinatorial NF-κB and HER2 inhibition has therapeutic benefit.