SIK2 Restricts Autophagic Flux To Support Triple-Negative Breast Cancer Survival

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery, and radiation. To identify new intervention targets in TNBC, we used large-scale, loss-of-function screening to identify molecular vulnerabilities among different oncogenomic backgrounds. This strategy returned salt inducible kinase 2 (SIK2) as essential for TNBC survival. Genetic or pharmacological inhibition of SIK2 leads to increased autophagic flux in both normal-immortalized and tumor-derived cell lines. However, this activity causes cell death selectively in breast cancer cells and is biased toward the claudin-low subtype. Depletion of ATG5, which is essential for autophagic vesicle formation, rescued the loss of viability following SIK2 inhibition. Importantly, we find that SIK2 is essential for TNBC tumor growth in vivo . Taken together, these findings indicate that claudin-low tumor cells rely on SIK2 to restrain maladaptive autophagic activation. Inhibition of SIK2 therefore presents itself as an intervention opportunity to reactivate this tumor suppressor mechanism

Comprehensive functional characterization of cancer–testis antigens defines obligate participation in multiple hallmarks of cancer

Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer–testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFβ signalling. In particular, we discover that Foetal and Adult Testis Expressed 1 (FATE1) is a key survival factor in multiple oncogenic backgrounds. FATE1 prevents the accumulation of the stress-sensing BH3-only protein, BCL-2-Interacting Killer (BIK), thereby permitting viability in the presence of toxic stimuli. Furthermore, ZNF165 promotes TGFβ signalling by directly suppressing the expression of negative feedback regulatory pathways. This action is essential for the survival of triple negative breast cancer cells in vitro and in vivo. Thus, CTAs make significant direct contributions to tumour biology

Disproportionate minority contact in Canada: Police and visible minority youth

There is a consensus that some racial groups are over-represented in their contact with the Canadian justice system, but a lack of agreement about possible reasons for this over-representation. The two dominant explanations for disproportionate minority contact (DMC) with the police are differential involvement in crime and differential treatment by the police. Differential treatment may be due to disproportionate possession by minorities of risk factors for police contact or to discriminatory policing. This paper uses data on self-reported delinquency and police contacts from a representative sample of Canadian youth aged 12 to 17 years from the National Longitudinal Study of Children and Youth to test the hypotheses that DMC is due to differential involvement or to differential treatment due to disproportionate risk factors. The results indicate that there was disproportionate minority contact with the police, but no support was found for explanations of DMC in terms of either differential involvement or differential treatment due to risk factors. Distinguishing between youth who report violent delinquency and all other youth, DMC was found only for the non-violent youth; this DMC was also not explained by differential treatment due to risk factors. By eliminating other explanations, the results suggest that racially discriminatory policing may be one explanation for DMC in Canada