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1.
Proc Natl Acad Sci U S A ; 119(46): e2207201119, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36343244

RESUMO

The transcription variation, leading to various forms of transcripts and protein diversity, remains largely unexplored in triple-negative breast cancers (TNBCs). Here, we presented a comprehensive analysis of RNA splicing in breast cancer to illustrate the biological function and clinical implications of tumor-specific transcripts (TSTs) arising from these splicing junctions. Aberrant RNA splicing or TSTs were frequently harbored in TNBC and were correlated with a poor outcome. We discovered a tumor-specific splicing variant of macrophage receptor with collagenous structure-TST (MARCO-TST), which was distinguished from myeloid cell-specific wild-type MARCO. MARCO-TST expression was associated with poor outcomes in TNBC patients and could promote tumor progression in vitro and in vivo. Mechanically, MARCO-TST interacted with PLOD2 and enhanced the stability of HIF-1α, which resulted in the metabolic dysregulation of TNBC to form a hypoxic tumor microenvironment. MARCO-TST was initiated from a de novo alternative transcription initiation site that was activated by a superenhancer. Tumors with MARCO-TST expression conferred greater sensitivity to bromodomain and extraterminal protein inhibitors. This treatment strategy was further validated in patient-derived organoids. In conclusion, our results revealed the transcription variation landscape of TNBC, highlighting MARCO-TST as a crucial oncogenic transcript and therapeutic target.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Carcinogênese/genética , Splicing de RNA , Proliferação de Células , Microambiente Tumoral
2.
Lancet Oncol ; 25(2): 184-197, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38211606

RESUMO

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , China , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
3.
Breast Cancer Res Treat ; 193(2): 319-330, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35334008

RESUMO

PURPOSE: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Patients with early-stage TNBCs have distinct likelihood of distant recurrence. This study aimed to develop a prognostic signature of early-stage TNBC patients to improve risk stratification. METHODS: Using RNA-sequencing data, we analyzed 189 pathologically confirmed pT1-2N0M0 TNBC patients and identified 21 mRNAs that were highly expressed in tumor and related to relapse-free survival. All-subset regression program was used for constructing a 7-mRNA signature in the training set (n = 159); the accuracy and prognostic value were then validated using an independent validation set (n = 158). RESULTS: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues. Early-stage TNBCs mainly consisted of basal-like immune-suppressed subtype and had higher homologous recombination deficiency scores. We developed a prognostic signature including seven mRNAs (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2). In both the training (n = 159) and validation set (n = 158), this signature could identify patients with relatively high recurrence risks and served as an independent prognostic factor. Time-dependent receiver operating curve showed that the signature had better prognostic value than traditional clinicopathological features in both sets. Functionally, we showed that TMEM101 promoted cell proliferation and migration in vitro, which represented a potential therapeutic target. CONCLUSIONS: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. This model may facilitate personalized therapy decision-making for early-stage TNBCs individuals.


Assuntos
Biomarcadores Tumorais , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Mensageiro/genética , Transcriptoma , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/terapia
4.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 37(1): 106-108, 2017 01.
Artigo em Zh | MEDLINE | ID: mdl-30695434

RESUMO

Objective In this paper the author summarized the contents of clinical research of Chinese medicine ( CM) and Western medicine (WM) from thinking methods based on literature re- search. He believed there were two kinds of main contents: (1) Combine CM syndrome typing and WM disease identification based on clinical experiences; (2) Limit the flexibility of CM syndrome typing within recognition of WM depending on modern scientific researches, thus realizing the integration of macrosyndrome typing and micro-disease identification. Based on these contents, the author expounded future development of CM and WM from future goals, tasks, feasible ways, and specific work.


Assuntos
Medicina Integrativa , Humanos , Medicina Tradicional Chinesa , Síndrome
5.
Biochem Biophys Res Commun ; 443(2): 598-603, 2014 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-24333432

RESUMO

Hypoxia-inducible factor 1α (HIF1α) is a transcription factor involved in the growth, invasion and metastasis of malignant tumors. Glycogen synthase kinase 3 beta (GSK3ß) is a protein kinase involved in a variety of signaling pathways, such as the Wnt and NF-κB pathways; this kinase can affect tumor progress through the regulation of transcription factor expression and apoptosis. Recent studies showed that GSK3ß was involved in the expression of HIF1α. However, the effect of GSK3ß on HIF1α expression in osteosarcoma cells remains unknown. To understand the relationship between GSK3ß and HIF1α comprehensively, small RNA interference techniques, Western blot analyses, quantitative real-time PCR analyses and luciferase assays were used in our study. Experimental data revealed that inhibition of GSK3ß could increase HIF1α protein levels and expression of its target genes by increasing the stability of the HIF1α mRNA, not by affecting the HIF1α protein stability, and that this process could be mediated by nucleolin.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Osteossarcoma/metabolismo , Fosfoproteínas/metabolismo , Estabilidade de RNA/fisiologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , RNA Mensageiro/genética , Nucleolina
6.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 33(8): 1135-7, 2013 Aug.
Artigo em Zh | MEDLINE | ID: mdl-24325069

RESUMO

The necessity of establishing an evaluation system about the combination program of Chinese medical pharmacy and Western medical pharmacy was addressed in this paper. Besides, its contents were systematically clarified. Besides, existent problems and its future development trend were also explained. The author believed that it was necessary to perform researches on constructing the evaluation system on the basis of patients' needs and physicians' responsibilities. The ultimate goal of this system was to produce an optimal combination program of Chinese medical pharmacy and Western medical pharmacy for a specific disease. This optimal program was the results of comparing and analyzing the therapeutic efficacies of different combination programs. In this program, Chinese medical pharmacy and Western medical pharmacy combined together. On the one hand, it is safe; on the other hand, they do not produce adverse reaction. Their therapeutic effects were synergetic. Chinese medical pharmacy could not only advance the cure effects of Western medical pharmacy, but also supplement the insufficiency of Western medical pharmacy. Of course, the author put forward some assumptions only from the perspective of clinical application in this paper. The evaluation system will become perfect along with further deepening researches of basic sciences.


Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Medicina Integrativa , Estudos de Avaliação como Assunto
7.
Cancer Res ; 83(10): 1711-1724, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37129951

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with unfavorable outcomes. Developing therapeutic targets for TNBC remains a challenge. Here, we identified that acetyl-CoA acyltransferase 1 (ACAA1) is highly expressed in the luminal androgen receptor (LAR) subtype of TNBC compared with adjacent normal tissues in our TNBC proteomics dataset. Inhibition of ACAA1 restrained TNBC proliferation and potentiated the response to the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib. Mechanistically, ACAA1 interacted with CDK4, and the inhibition of ACAA1 blocked RB transcriptional corepressor 1 (RB1) phosphorylation, resulting in G1-S cell-cycle arrest. Importantly, trimetazidine, a traditional drug for ischemic heart disease, caused a decrease in ACAA1 protein levels and enhanced the efficacy of abemaciclib in preclinical TNBC models. In conclusion, this study identifies that ACAA1 is a therapeutic target in TNBC and suggests the combination of trimetazidine and abemaciclib could be beneficial for ACAA1-high TNBCs. SIGNIFICANCE: ACAA1 is highly expressed in TNBC, serving as a potential therapeutic target in ACAA1-high tumors and a predictive biomarker of resistance to CDK4/6 inhibitors for RB1-proficient patients.


Assuntos
Trimetazidina , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Trimetazidina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinase 4 Dependente de Ciclina , Acetil-CoA C-Aciltransferase
8.
Clin Transl Med ; 12(5): e825, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35522895

RESUMO

AIMS: MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented. METHODS AND RESULTS: We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition. CONCLUSION: We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application.


Assuntos
Antineoplásicos , Neoplasias da Mama , Fatores de Transcrição , Adenosina Trifosfatases/genética , Antineoplásicos/farmacologia , Autofagia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Humanos , Proteínas Oncogênicas
9.
Cell Res ; 32(5): 477-490, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35105939

RESUMO

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.


Assuntos
Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Humanos , Metabolômica , Medicina de Precisão , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
10.
Oncogene ; 40(12): 2323-2334, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33654196

RESUMO

Progression of triple-negative breast cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast cancer metastasis, we performed RNA sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.


Assuntos
Desacetilase 6 de Histona/genética , Inibidores de Histona Desacetilases/farmacologia , Proteínas dos Microtúbulos/genética , Neoplasias de Mama Triplo Negativas/genética , Tubulina (Proteína)/genética , Acetilação/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Metástase Neoplásica , Pirimidinas/farmacologia , Análise de Sequência de RNA , Neoplasias de Mama Triplo Negativas/patologia , Sequenciamento do Exoma
11.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34281987

RESUMO

PURPOSE: Regulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC. EXPERIMENTAL DESIGN: Using the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism. RESULTS: We revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy. CONCLUSIONS: Tumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.


Assuntos
GTP Cicloidrolase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Linfócitos T Reguladores/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Animais , Feminino , Humanos , Camundongos , Regulação para Cima
12.
Clin Transl Med ; 11(11): e589, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34842356

RESUMO

BACKGROUND: Few studies have discussed the contradictory roles of mutated-PI3Kα in HER2-positive (HER2+) breast cancer. Thus, we characterised the adaptive roles of PI3Kα mutations among HER2+ tumour progression. METHODS: We conducted prospective clinical sequencing of 1923 Chinese breast cancer patients and illustrated the clinical significance of PIK3CA mutations in locally advanced and advanced HER2+ cohort. A high-throughput PIK3CA mutations-barcoding screen was performed to reveal impactful mutation sites in tumour growth and drug responses. RESULTS: PIK3CA mutations acted as a protective factor in treatment-naïve patients; however, advanced/locally advanced patients harbouring mutated-PI3Kα exhibited a higher progressive disease rate (100% vs. 15%, p = .000053) and a lower objective response rate (81.7% vs. 95.4%, p = .0008) in response to trastuzumab-based therapy. Meanwhile, patients exhibiting anti-HER2 resistance had a relatively high variant allele fraction (VAF) of PIK3CA mutations; we defined the VAF > 12.23% as a predictor of poor anti-HER2 neoadjuvant treatment efficacy. Pooled mutations screen revealed that specific PI3Kα mutation alleles mediated own biological effects. PIK3CA functional mutations suppressed the growth of HER2+ cells, but conferred anti-HER2 resistance, which can be reversed by the PI3Kα-specific inhibitor BYL719. CONCLUSIONS: We proposed adaptive treatment strategies that the mutated PIK3CA and amplified ERBB2 should be concomitantly inhibited when exposing to continuous anti-HER2 therapy, while the combination of anti-HER2 and anti-PI3Kα treatment was not essential for anti-HER2 treatment-naïve patients. These findings improve the understanding of genomics-guided treatment in the different progressions of HER2+ breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Análise de Sequência/estatística & dados numéricos , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/genética , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , China , Estudos de Coortes , Feminino , Humanos , Estudos Prospectivos , Análise de Sequência/métodos
13.
Cell Metab ; 33(1): 51-64.e9, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33181091

RESUMO

Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.


Assuntos
Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Feminino , Humanos , Imunoterapia , Masculino , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/terapia , Células Tumorais Cultivadas
14.
Theranostics ; 10(24): 10940-10956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042263

RESUMO

Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/epidemiologia , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/terapia , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Animais , Mama/patologia , Mama/cirurgia , Linhagem Celular Tumoral , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Microscopia Intravital , Mastectomia , Camundongos , Microtúbulos/metabolismo , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/genética , Organoides , Paclitaxel/uso terapêutico , Prognóstico , Multimerização Proteica/genética , RNA-Seq , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas , Proteínas de Transporte Vesicular/metabolismo , Adulto Jovem
15.
Nat Commun ; 11(1): 5679, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173047

RESUMO

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.


Assuntos
Povo Asiático/genética , Neoplasias da Mama , Terapia de Alvo Molecular , Mutação , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , China , Gerenciamento de Dados , Feminino , Marcadores Genéticos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neurofibromina 2/genética , Oncogenes , Medicina de Precisão , Estudos Prospectivos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética
16.
Transl Cancer Res ; 8(2): 614-625, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35116794

RESUMO

BACKGROUND: Whether primary tumor surgery should be performed in breast cancer patients with metastatic disease at diagnosis has been debated for decades. This study aims to evaluate the value of primary tumor surgery with respect to the mortality of patients with de novo stage IV breast cancer and to define the heterogeneity of this population. METHODS: De novo stage IV patients from the Surveillance, Epidemiology and End Results database (SEER) from 2010 to 2015 were included in our study. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to achieve balanced baseline characteristics. The effect of surgery was assessed by Kaplan-Meier curves and Cox regression models. RESULTS: Of the 11,684 patients eligible for analysis, 3,730 (31.92%) received primary tumor surgery. Multivariate Cox regression in the PSM cohort revealed that surgery was associated with better outcomes than those in the nonsurgery group in terms of overall survival (OS) [hazard ratio (HR): 0.51; 95% CI: 0.48-0.55; P<0.001] and breast cancer-specific survival (BCSS) (HR: 0.51; 95% CI: 0.47-0.55; P<0.001). IPTW analysis yielded similar results. In a subgroup analysis, surgery was associated with better survival in all subtypes with low metastatic burdens (≤2 metastatic sites), but triple-negative breast cancer with a high metastatic burden (>2 metastatic sites) did not benefit from surgery (HR: 0.78; 95% CI: 0.31-1.97, P=0.596 and 0.78, 95% CI: 0.31-1.97, P=0.596 for OS and BCSS, respectively). CONCLUSIONS: Primary tumor surgery significantly prolonged the survival of patients with de novo stage IV breast cancer. However, triple-negative breast cancer patients with more than two metastatic sites may not benefit from surgery.

17.
Cancer Cell ; 35(3): 428-440.e5, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30853353

RESUMO

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/classificação , Povo Asiático/genética , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 22/genética , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Metástase Neoplásica , Prognóstico , Neoplasias de Mama Triplo Negativas/genética
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