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.

c 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 claudinlow 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. Breast cancer is an extremely heterogeneous disease that is classified by the presence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Cases where Ͻ1% of cells express ER, PR, or HER2 are considered triple-negative breast cancer (TNBC) (1). These molecular markers can serve as a critical stratification tool for tailoring effective therapies to sensitive patients. For example, antiestrogens such as tamoxifen are highly effective in ER-positive patients, and HER2-positive tumors are responsive to trastuzumab (2, 3). Conversely, TNBC tumors lack these targetable proteins, limiting first-line treatment to a combination of radiation and chemotherapy. This approach has changed little over the last 20 years and is characterized by high toxicity and frequent relapse of chemorefractory disease (4). Furthermore, levels of overall and disease-free survival in TNBC are significantly worse than those of other subgroups of breast cancer (5). Thus, for TNBC there is a dire need for less toxic therapies that target the major fulcrums supporting tumor cell survival.In addition to clinical and pathological markers, extensive gene expression profiling efforts by a number of groups have identified multiple intrinsic molecular subtypes within breast cancer. These subtypes include luminal A and B, which comprise the majority of ER-and PR-positive cases, as well a HER2-enriched clade. Importantly, this analysis has revealed substantial heterogeneity within TNBC. Broadly, TNBC can be subclassified into 2 intrinsic subtypes, basal like and claudin low, but up to 6 additional subclasses have been identified (6-9). Significantly, these groups can...

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