Autophagy Inhibition as a Potential Therapeutic Strategy for Breast Cancer with Mitochondrial Translation Defect Caused by CBFB-Deficiency.

ABBREVIATIONS: AMPK, AMP-activated protein kinase; BioID, biotinylation identification; CBFB, core-binding factor subunit beta; HCQ, hydroxychloroquine; HNRNPK, heterogeneous nuclear ribonucleoprotein K; PDX, patient-derived xenograft; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; TUFM, Tu translation elongation factor, mitochondrial; ETC, electron transport chain.

Dysregulation of Mitochondrial Translation Caused by CBFB Deficiency Cooperates with Mutant PIK3CA and Is a Vulnerability in Breast Cancer.

Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated cancer pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger pairs remains challenging. Here, we designed an integrated omics approach to identify driver gene pairs by leveraging genetic interaction analyses of top mutated breast cancer genes and the proteomics interactome data of their encoded proteins. This approach identified that PIK3CA oncogenic gain-of-function (GOF) and CBFB loss-of-function (LOF) mutations cooperate to promote breast tumor progression in both mice and humans. The transcription factor CBFB localized to mitochondria and moonlighted in translating the mitochondrial genome. Mechanistically, CBFB enhanced the binding of mitochondrial mRNAs to TUFM, a mitochondrial translation elongation factor. Independent of mutant PI3K, mitochondrial translation defects caused by CBFB LOF led to multiple metabolic reprogramming events, including defective oxidative phosphorylation, the Warburg effect, and autophagy/mitophagy addiction. Furthermore, autophagy and PI3K inhibitors synergistically killed breast cancer cells and impaired the growth of breast tumors, including patient-derived xenografts carrying CBFB LOF and PIK3CA GOF mutations. Thus, our study offers mechanistic insights into the functional interaction between mutant PI3K and mitochondrial translation dysregulation in breast cancer progression and provides a strong preclinical rationale for combining autophagy and PI3K inhibitors in precision medicine for breast cancer. SIGNIFICANCE: CBFB-regulated mitochondrial translation is a regulatory step in breast cancer metabolism and synergizes with mutant PI3K in breast cancer progression.

An Updated View of the Roles of p53 in Embryonic Stem Cells.

The TP53 gene is unarguably one of the most studied human genes. Its encoded protein, p53, is a tumor suppressor and is often called the "guardian of the genome" due to its pivotal role in maintaining genome stability. Historically, most studies of p53 have focused on its roles in somatic cells and tissues, but in the last 2 decades, its functions in embryonic stem cells (ESCs) and induced pluripotent stem cells have attracted increasing attention. Recent studies have identified p53 as a critical regulator of pluripotency, self-renewal, differentiation, proliferation, and genome stability in mouse and human embryonic stem cells. In this article, we systematically review the studies on the functions of p53 in ESCs, provide an updated overview, attempt to reconcile controversial results described in the literature, and discuss the relevance of these cellular functions of p53 to its roles in tumor suppression.

Fatty acid oxidation is required for embryonic stem cell survival during metabolic stress.

Metabolic regulation is critical for the maintenance of pluripotency and the survival of embryonic stem cells (ESCs). The transcription factor Tfcp2l1 has emerged as a key factor for the naïve pluripotency of ESCs. Here, we report an unexpected role of Tfcp2l1 in metabolic regulation in ESCs-promoting the survival of ESCs through regulating fatty acid oxidation (FAO) under metabolic stress. Tfcp2l1 directly activates many metabolic genes in ESCs. Deletion of Tfcp2l1 leads to an FAO defect associated with upregulation of glucose uptake, the TCA cycle, and glutamine catabolism. Mechanistically, Tfcp2l1 activates FAO by inducing Cpt1a, a rate-limiting enzyme transporting free fatty acids into the mitochondria. ESCs with defective FAO are sensitive to cell death induced by glycolysis inhibition and glutamine deprivation. Moreover, the Tfcp2l1-Cpt1a-FAO axis promotes the survival of quiescent ESCs and diapause-like blastocysts induced by mTOR inhibition. Thus, our results reveal how ESCs orchestrate pluripotent and metabolic programs to ensure their survival in response to metabolic stress.

CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer.

The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Here, we analyze genetic interactions between mutations of CBFB and other highly mutated genes in human breast cancer datasets and find that CBFB and TP53 mutations are mutually exclusive, suggesting a functional association between CBFB and p53. Integrated genomic studies reveal that TAp73 is a common transcriptional target of CBFB and p53. CBFB cooperates with p53 to maintain TAp73 expression, as either CBFB or p53 loss leads to TAp73 depletion. TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion. Although TAp73 loss alone is insufficient for tumorigenesis, it enhances the tumorigenic effect of NOTCH3 overexpression, a downstream event of CBFB loss. Immunohistochemistry shows that p73 loss is coupled with higher proliferation in xenografts. Moreover, TAp73 loss-of-expression is a frequent event in human breast cancer tumors and cell lines. Together, our results significantly advance our understanding of the tumor suppressive functions of CBFB and reveal a mechanism underlying the communication between the two tumor suppressors CBFB and p53.

The transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription.

Translation and transcription are frequently dysregulated in cancer. These two processes are generally regulated by distinct sets of factors. The CBFB gene, which encodes a transcription factor, has recently emerged as a highly mutated driver in a variety of human cancers including breast cancer. Here we report a noncanonical role of CBFB in translation regulation. RNA immunoprecipitation followed by deep sequencing (RIP-seq) reveals that cytoplasmic CBFB binds to hundreds of transcripts and regulates their translation. CBFB binds to mRNAs via hnRNPK and enhances translation through eIF4B, a general translation initiation factor. Interestingly, the RUNX1 mRNA, which encodes the transcriptional partner of CBFB, is bound and translationally regulated by CBFB. Furthermore, nuclear CBFB/RUNX1 complex transcriptionally represses the oncogenic NOTCH signaling pathway in breast cancer. Thus, our data reveal an unexpected function of CBFB in translation regulation and propose that breast cancer cells evade translation and transcription surveillance simultaneously through downregulating CBFB.

Effectiveness of brief cognitive-behavioral therapy for schizophrenia delivered by mental health nurses: relapse and recovery at 24 months.

BACKGROUND: Evidence of the efficacy of cognitive-behavioral therapy (CBT) for schizophrenia is increasing. There are very few studies of effectiveness, especially in the medium term. OBJECTIVE: To evaluate the durability of the effect of brief CBT provided by mental health nurses in community-based patients with schizophrenia (diagnosed according to ICD-10 research criteria), using time to relapse as primary outcome and days hospitalized and occupational recovery as secondary outcomes at 24-month follow-up. METHOD: A 2:1 randomized trial, conducted from 1999 to 2003, was performed to evaluate the effects of brief CBT delivered by mental health nurses trained over 10 days with ongoing supervision compared to treatment as usual (TAU), with measurement performed by raters blind to treatment allocation. RESULTS: 205 (79.8%) of 257 CBT patients and 125 (75.8%) of 165 TAU patients could be followed up at 24 months. Of 205 patients in the CBT group, 64 (31.2%) relapsed, versus 57 (45.6%) of 125 patients in the TAU group (p = .02). Patients rehospitalized from the CBT group spent a total of 6710 days in hospital (mean = 32.7 days), while those from the TAU group were inpatients for 6114 days (mean = 48.9 days) (p < .05). Twenty-one (10.2%) of 205 patients made an occupational recovery in the CBT group, and 17 (13.6%) of 125, in the TAU group (chi(2) test not significant). Mean time to relapse was 356.8 days (SD = 241.9 days) for the CBT group and 296.1 days (SD = 215.7 days) for the TAU group (OR = 1.592, 95% CI = 1.038 to 2.441, p = .033). CONCLUSION: Beneficial effects on relapse and rehospitalization following brief CBT delivered by mental health nurses in community-based patients with schizophrenia are maintained at 24-month follow-up. Occupational recovery is not improved by brief CBT.

Temporal stability of the dex/CRH test in patients with rapid-cycling bipolar I disorder: a pilot study.

OBJECTIVE: To examine the hypothesis that hypothalamic-pituitary-adrenal (HPA) axis function is a trait abnormality in bipolar disorder. METHOD: We examined HPA axis function in a pilot study of five patients with rapid-cycling bipolar disorder in both relapse and remission using the dexamethasone/corticotropin releasing hormone (dex/CRH) test. RESULTS: The cortisol response to the dex/CRH test correlated significantly between the 2 tests (r = 0.997; p < 0.0005). CONCLUSION: The data suggests that the cortisol response to the dex/CRH test is stable over time and independent of mood state.