Metastasis to the lungs is a leading cause of death for patients with breast cancer. Therefore, effective therapies are urgently needed to prevent and treat lung metastasis. In this study, we uncovered a mechanism by which NAD(P)H:quinone oxidoreductase 1 (NQO1) orchestrates lung metastasis. NQO1 stabilized and upregulated peptidyl-prolyl cis-trans isomerase A (PPIA), a chaperone that regulates protein conformation and activity, by preventing its oxidation at a critical cysteine residue C161. PPIA subsequently activated CD147, a membrane protein that facilitates cell invasion. Moreover, NQO1-induced secretion of PPIA modulated the immune landscape of both primary and lung metastatic sites. Secreted PPIA engaged CD147 on neutrophils and triggered the release of neutrophil extracellular traps (NET) and neutrophil elastase, which enhanced tumor progression, invasiveness, and lung colonization. Pharmacological targeting of PPIA effectively inhibited NQO1-mediated breast cancer lung metastasis. These findings reveal a previously unrecognized NQO1-PPIA-CD147-NET axis that drives breast cancer lung metastasis. Inhibiting this axis is a potential therapeutic strategy to limit lung metastasis in patients with breast cancer. Significance: NQO1 stabilizes and promotes the secretion of PPIA to activate CD147 in neutrophils and stimulate NET formation, promoting breast cancer lung metastasis and providing therapeutic targets for this fatal condition.

Secreted angiopoietin/angiopoietin-like (ANGPT/ANGPTL) proteins are involved in many biological processes. However, the role of these proteins in human breast cancers (BCs) remains largely unclear. Here, we conducted integrated omics analyses to evaluate the clinical impact of ANGPT/ANGPTL proteins and to elucidate their biological functions. In BCs, we identified rare mutations in ANGPT/ANGPTL genes, frequent gains of ANGPT1, ANGPT4, and ANGPTL1, and frequent losses of ANGPT2, ANGPTL5, and ANGPTL7, but observed that ANGPTL1, 2, and 4 were robustly downregulated in multiple datasets. The expression levels of ANGPTL1, 5, and 8 were positively correlated with overall survival (OS), while the expression levels of ANGPTL4 were negatively correlated with OS. Additionally, the expression levels of ANGPTL1 and 7 were positively correlated with distant metastasis-free survival (DMFS), while the expression levels of ANGPT2 and ANGPTL4 were negatively correlated with DMFS. The prognostic impacts of ANGPT/ANGPTL genes depended on the molecular subtypes and on clinical factors. We discovered that various ANGPT/ANGPTL genes were co-expressed with various genes involved in different pathways. Finally, with the exception of ANGPTL3, the remaining genes showed significant correlations with cancer-associated fibroblasts, endothelial cells, and microenvironment score, whereas only ANGPTL6 was significantly correlated with immune score. Our findings provide strong evidence for the distinct clinical impact and biological function of ANGPT/ANGPTL proteins, but the question of whether some of them could be potential therapeutic targets still needs further investigation in BCs.

Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice. Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment. Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC. The U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the "European Union Next Generation EU/PRTR," the Regional Government of Castile and León (CSI144P20), European Union.

Background: Anlotinib is an oral anti-angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, fibroblast growth factor receptors, etc., and its clinical value in cervical cancer is rarely reported. We designed a retrospective study to evaluate the efficacy and safety of anlotinib in patients with persistent, metastatic, or recurrent cervical cancer who have failed first-line therapy, and compare the efficacy of anlotinib with that of apatinib which targets only VEGFR2 and has shown efficacy in recent studies. Methods: Fifty-two patients with persistent, metastatic, or recurrent cervical cancer who failed first-line therapy and administrated anlotinib or apatinib as monotherapy or combination with chemo-, radio- or immunotherapy were included in this study. Among the 52 patients, 20 patients who received anlotinib from January 2019 to August 2020 were defined as anlotinib group, whereas 32 patients who received apatinib from our previous study were selected as apatinib group. The safety, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and recorded. Results: The ORR and DCR in patients receiving anlotinib were 25% and 80%, respectively. The median PFS and OS in anlotinib group were significantly longer than those in apatinib group, respectively (PFS: 5 months vs 3 months, p=0.015; OS: 10 months vs 5 months, p=0.008). Moreover, the patients treated with anlotinib had better survival with a significantly lower cumulative incidence of cancer-related death than those treated with apatinib (HR=0.31, 95% CI: 0.13– 0.77, p=0.012). The most common adverse effects in the patients treated with anlotinib were hypertension (20%), fatigue (20%), and nausea (15%). No drug-related death occurred. Conclusion: Anlotinib showed beneficial efficacy and safety and can be a treatment option for patients with persistent, metastatic, or recurrent cervical cancer who have failed the first-line therapy.

Background: Apatinib is an oral anti‐angiogenic drug, its efficacy and prognosis in cervical carcinoma are unclear. This study evaluates the effectiveness and prognostic factors of apatinib in the treatment of recurrent or advanced cervical carcinoma.Methods: Patients with recurrent or advanced cervical cancer, who agreed to take apatinib, were recruited into this single‐center and retrospective study, and administrated apatinib with or without combination of chemo‐ or radio‐therapy until progressive disease (PD) or unacceptable toxicity.Results: From March 2017 to February 2019, 53 patients were reviewed. Among them, 2 (3.77%) patients occurred complete response, 16 (30.19%) patients showed partial response, 27 (50.95%) patients had stable disease, and 8 (15.09%) patients had PD. The objective response rate and disease control rate (DCR) of these patients were 33.96% and 84.91%, respectively. The DCR of patients younger than 50, nonsquamous carcinoma, first‐line apatinib therapy, combined radiotherapy, lesions within radiation field, surgical history, and Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 were significantly higher than other patients (p < 0.05). The median progression‐free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.43–7.57) and 8.0 months (95% CI: 6.52–9.48), respectively. The univariable and multivariable analysis showed that the patients with an ECOG performance status score of 2 and further line therapy were associated with poor prognosis in both PFS and OS (PFS: HR =8.35, p = 0.000; HR =6.66, p = 0.001; OS: HR = 7.40, p = 0.000; HR = 3.24, p = 0.039), respectively. The most common adverse effects (AEs) were hand‐foot syndrome (35.58%), hypertension (18.87%) and fatigue (15.09%). No grade 3 AEs and drug‐related death occurred.Conclusion: The efficacy and prognosis of patients who are in good general condition and first‐line apatinib combination therapy may be better than other patients. But further phase III clinical trials should be taken to prove this hypothesis.

This file includes: Materials and Methods; Figures. S1 to S22; Tables. S1, S2, S3, S4, S5 and S7; Original Western-blot images