Genetic Dissection of Therapeutic Intervention Targets in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is the most aggressive and metastatic type of breast cancer, accounting for 20% of all breast cancer diagnoses. Currently, there are no TNBC-specific targeted therapies in the clinic and therefore, broad-spectrum cytotoxic chemotherapeutic regimens remain the standard of care. Due to high rates of innate drug resistance, many TNBC patients do not respond to these regimens and, therefore, have no other therapeutic options. Our group employed a pan-genomic loss of function screen to systematically dissect the molecular architecture that functionally supports TNBC to uncover new therapeutic entry points. We further applied a paclitaxel-based synthetic lethal approach to increase our discovery space to also identify those molecular components that modulate chemoresponsiveness. To encompass the heterogeneity found within the TNBC patient population, we screened four triple negative tumor-derived breast cancer cell lines that represent the spectrum of TNBC oncogenic aberrations and chemoresponse profiles. We also accounted for the two molecular subtypes, claudin-low and basal-like that comprise the majority of TNBC cases. These screens revealed a number of core modulators of tumor cell viability and paclitaxel-induced cellular stress that have not been previously appreciated for supporting TNBC biology at the cell autonomous level. In particular, this strategy implicated the signaling supported by the cytokine receptor, CXCR3, and its ligand, CXCL9, to promote mitotic fidelity and tumor cell survival in the basal-like TNBC molecular subtype. In addition, we uncovered a requirement for the AMPK family member, SIK2, as a key nutrient sensor that may inhibit excessive autophagy. Inhibition of SIK2 enhanced autophagic flux and a loss of cell viability in a variety of TNBC genetic backgrounds. Finally, we discovered that cancer testes antigen transcription factor, ZNF165, directly repressed expression of negative TGFβ regulators thereby specifying a pro-tumorigenic TGFβ gene expression profile. Given that the expression of ZNF165 is otherwise restricted to the male testes, ZNF165 may represent a mechanism by which tumors engage anomaly-expressed proteins to promote survival. Taken together, our screening approach uncovered novel TNBC tumor cell vulnerabilities that identified cellular processes that could lead to new therapeutic approaches.Doctor of Philosoph

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

Predictors of multiple arrests among homeless young adults: Gender differences

Criminological research on homeless young adults has shown that males are more often arrested for violent offenses, while females engage more frequently in self-destructive behaviors. General strain theory (GST) provides a useful theoretical framework for understanding criminal behaviors and arrest history among homeless young adults. This study examined strains and responses to strains that significantly predict the likelihood of multiple arrests and investigated how predictors of multiple arrests vary by gender. Findings indicate that predictors for multiple arrests do indeed vary by gender, with exposure to the drug culture of the streets being an important variable for males, while being robbed with a weapon and drug distribution are significant predictors for females. Resilience showed an inverse relationship with multiple arrests, as did sexual assault for females. Study findings and implications for service provision are discussed