Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.

BackgroundOccult breast cancer (OBC) is a rare type of breast cancer that has not been well studied. The clinicopathological characteristics and treatment recommendations for OBC are based on a limited number of retrospective studies and thus remain controversial.Patients and methodsWe identified 479 OBC patients and 115,739 non-OBC patients from 2004 to 2014 in and the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological characteristics and survival outcomes were compared between OBC and non-OBC patients. We used the propensity score 1:1 matching analysis to evaluate OBC vs non-OBC comparison using balanced groups with respect to the observed covariates. We further divided the OBC population into four groups based on different treatment strategies. Univariable and multivariable analyses were used to calculate and compare the four treatment outcomes within the OBC population.ResultsOBC patients were older, exhibited a more advanced stage, a higher rate of negative estrogen receptor and progesterone receptor status, a higher rate of HER2-positive status, and a higher rate of ≥10 positive lymph nodes, and were less likely to undergo surgical treatment than non-OBC patients. After adjustments for clinicopathological factors, the OBC patients exhibited a significantly better survival than the non-OBC patients (P<0.001). This result was confirmed in a 1:1 matched case–control analysis. Within the four OBC treatment groups, we observed no difference in survival among the mastectomy group, the breast-conserving surgery (BCS) group, and the axillary lymph node dissection (ALND)-only group. The multivariable analysis revealed that the sentinel lymph node dissection-only group had the worst prognosis (P<0.001). Conclusion: OBC has unique clinicopathological characteristics and a favorable prognosis compared with non-OBC. BCS plus ALND and radiotherapy showed a survival benefit that was similar to that of mastectomy for OBC patients.

Previous studies have suggested an association between preoperative plasma fibrinogen and D-dimer levels and prognosis in patients with non-small cell lung cancer (NSCLC) who underwent surgery. In this study, we evaluate the value of pre- and post-operative plasma fibrinogen and D-dimer levels and changes in the levels of the two markers between before and after operation in predicting tumor recurrence and metastasis in NSCLC patients who undergoing radical surgery. One hundred and eighty-four patients with I-IIIA NSCLC were enrolled in this study, and plasma fibrinogen and D-dimer levels were measured in these patients before and after surgery, respectively. The results showed that pre- and post-operative plasma fibrinogen and D-dimer levels were significantly higher in NSCLC patients than in control group. Pre- and post-operative plasma fibrinogen and D-dimer positivities were significantly correlated with tumor recurrence (P = 0.020 and P = 0.001 for fibrinogen, and P = 0.027 and P = 0.001 for D-dimer). Moreover, there was a significant link between the decrease in fibrinogen and D-dimer levels after surgery and tumor recurrence (P = 0.014 and P = 0.018). Patients with pre- and post-operative fibrinogen and D-dimer positivities had a shorter disease-free survival (DFS) than those without (P = 0.002 and P < 0.001 for fibrinogen, and P = 0.003 and P = 0.001 for D-dimer). Multivariate Cox regression analyses revealed that pre- and post-operative fibrinogen and D-dimer positivities were independent predictors for unfavorable DFS. Our results indicate that pre- and post-operative plasma fibrinogen and D-dimer levels may be useful biomarkers in predicting tumor recurrence and metastasis for patients who undergo curative surgery.

Background: Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer. Methods: The expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoid were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays. Results: Herein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoid to the CDK4/6 inhibitor palbociclib both in vitro and in vivo. Conclusions: TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.