Evading cancer drugs by identity fraud: Prostate cancer growth is fueled by male hormones called androgens. Drugs targeting the androgen receptor (AR) are initially efficacious, but most tumors eventually become resistant (see the Perspective by Kelly and Balk). Mu et al. found that prostate cancer cells escaped the effects of androgen deprivation therapy through a change in lineage identity. Functional loss of the tumor suppressors TP53 and RB1 promoted a shift from AR-dependent luminal epithelial cells to AR-independent basal-like cells. In related work, Ku et al. found that prostate cancer metastasis, lineage switching, and drug resistance were driven by the combined loss of the same tumor suppressors and were accompanied by increased expression of the epigenetic regulator Ezh2. Ezh2 inhibitors reversed the lineage switch and restored sensitivity to androgen deprivation therapy in experimental models. Science , this issue p. 84 , p. 78 ; see also p. 29

Evading cancer drugs by identity fraud: Prostate cancer growth is fueled by male hormones called androgens. Drugs targeting the androgen receptor (AR) are initially efficacious, but most tumors eventually become resistant (see the Perspective by Kelly and Balk). Mu et al. found that prostate cancer cells escaped the effects of androgen deprivation therapy through a change in lineage identity. Functional loss of the tumor suppressors TP53 and RB1 promoted a shift from AR-dependent luminal epithelial cells to AR-independent basal-like cells. In related work, Ku et al. found that prostate cancer metastasis, lineage switching, and drug resistance were driven by the combined loss of the same tumor suppressors and were accompanied by increased expression of the epigenetic regulator Ezh2. Ezh2 inhibitors reversed the lineage switch and restored sensitivity to androgen deprivation therapy in experimental models. Science , this issue p. 84 , p. 78 ; see also p. 29

The miR-17∼92 cluster is frequently amplified or overexpressed in human cancers and has emerged as the prototypical oncogenic polycistron microRNA (miRNA). miR-17∼92 is a direct transcriptional target of c-Myc, and experiments in a mouse model of B-cell lymphomas have shown cooperation between these two oncogenes. However, both the molecular mechanism underlying this cooperation and the individual miRNAs that are responsible for it are unknown. By using a conditional knockout allele of miR-17∼92, we show here that sustained expression of endogenous miR-17∼92 is required to suppress apoptosis in Myc-driven B-cell lymphomas. Furthermore, we show that among the six miRNAs that are encoded by miR-17∼92, miR-19a and miR-19b are absolutely required and largely sufficient to recapitulate the oncogenic properties of the entire cluster. Finally, by combining computational target prediction, gene expression profiling, and an in vitro screening strategy, we identify a subset of miR-19 targets that mediate its prosurvival activity.

An obligate intermediate during microRNA (miRNA) biogenesis is an ∼22-nucleotide RNA duplex, from which the mature miRNA is preferentially incorporated into a silencing complex. Its partner miRNA* species is generally regarded as a passenger RNA, whose regulatory capacity has not been systematically examined in vertebrates. Our bioinformatic analyses demonstrate that a substantial fraction of miRNA* species are stringently conserved over vertebrate evolution, collectively exhibit greatest conservation in their seed regions, and define complementary motifs whose conservation across vertebrate 3′-UTR evolution is statistically significant. Functional tests of 22 miRNA expression constructs revealed that a majority could repress both miRNA and miRNA* perfect match reporters, and the ratio of miRNA:miRNA* sensor repression was correlated with the endogenous ratio of miRNA:miRNA* reads. Analysis of microarray data provided transcriptome-wide evidence for the regulation of seed-matched targets for both mature and star strand species of several miRNAs relevant to oncogenesis, including mir-17, mir-34a, and mir-19. Finally, 3′-UTR sensor assays and mutagenesis tests confirmed direct repression of five miR-19* targets via star seed sites. Overall, our data demonstrate that miRNA* species have demonstrable impact on vertebrate regulatory networks and should be taken into account in studies of miRNA functions and their contribution to disease states.

Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.

MicroRNAs belonging to the miR-34 family have been proposed as critical modulators of the p53 pathway and potential tumor suppressors in human cancers. To formally test these hypotheses, we have generated mice carrying targeted deletion of all three members of this microRNA family. We show that complete inactivation of miR-34 function is compatible with normal development in mice. Surprisingly, p53 function appears to be intact in miR-34–deficient cells and tissues. Although loss of miR-34 expression leads to a slight increase in cellular proliferation in vitro, it does not impair p53-induced cell cycle arrest or apoptosis. Furthermore, in contrast to p53-deficient mice, miR-34–deficient animals do not display increased susceptibility to spontaneous, irradiation-induced, or c-Myc–initiated tumorigenesis. We also show that expression of members of the miR-34 family is particularly high in the testes, lungs, and brains of mice and that it is largely p53-independent in these tissues. These findings indicate that miR-34 plays a redundant function in the p53 pathway and suggest additional p53-independent functions for this family of miRNAs. MicroRNAs (miRNAs) are small, non-coding RNAs that broadly regulate gene expression. MicroRNA deregulation is a common feature of human cancers, and numerous miRNAs have oncogenic or tumor suppressive properties. Members of the miR-34 family (miR-34a, miR-34b, and miR-34c) have been widely speculated to be important tumor suppressors and mediators of p53 function. Despite the growing body of evidence supporting this hypothesis, previous studies on miR-34 have been done in vitro or using non-physiologic expression levels of miR-34. Here, we probe the tumor suppressive functions of the miR-34 family in vivo by generating mice carrying targeted deletion of the entire miR-34 family. Our results show that the miR-34 family is not required for tumor suppression in vivo, and they suggest p53-independent functions for this family of miRNAs. Importantly, the mice generated from this study provide a tool for the scientific community to further investigate the physiologic functions of the miR-34 family.