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Although interleukin 1 (IL-1) induces expression of the transcription factor IRF1 (interferon-regulatory factor 1), the roles of IRF1 in immune and inflammatory responses and mechanisms of its activation remain elusive. Here we found that IRF1 was essential for IL-1-induced expression of the chemokines CXCL10 and CCL5, which recruit mononuclear cells into sites of sterile inflammation. Newly synthesized IRF1 acquired Lys63 (K63)-linked polyubiquitination mediated by the apoptosis inhibitor cIAP2 that was enhanced by the bioactive lipid S1P. In response to IL-1, cIAP2 and the sphingosine kinase SphK1 (the enzyme that generates S1P) formed a complex with IRF1, which led to its activation. Thus, IL-1 triggered a hitherto unknown signaling cascade that controlled the induction of IRF1-dependent genes that encode molecules important for sterile inflammation.
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Quimiocina CCL5/biossíntese , Quimiocina CXCL10/biossíntese , Fator Regulador 1 de Interferon/metabolismo , Interleucina-1/metabolismo , Transdução de Sinais/imunologia , Animais , Quimiocina CCL5/imunologia , Quimiocina CXCL10/imunologia , Quimiotaxia de Leucócito/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Immunoblotting , Imunoprecipitação , Inflamação/imunologia , Inflamação/metabolismo , Fator Regulador 1 de Interferon/imunologia , Interleucina-1/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lisina , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , UbiquitinaçãoRESUMO
OBJECTIVE: To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME). BACKGROUND: The role of rare cells in TME is less studied. In Silico transcriptomic analyses of real-world data enable us to detect and quantify rare cells, including CMP cells. METHODS: Total of 5,176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using xCell algorithm. High group was defined as more than two thirds of CMP score in each cohort. RESULTS: CMP cells consist of 0.07-0.25% of bulk breast tumor cells, more in Estrogen Receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1-0.75%, 0.18-0.33% of immune cells, respectively). CMP cells did not correlate with any of myeloid lineage nor stem cells in TME. CMP infiltration was higher in smaller tumors, with lower Nottingham grade, and in ER+/HER2- than in TNBC consistently in both SCAN-B and METABRIC cohorts. High CMP was significantly associated with lower risk of brain metastasis and with better survival, particularly in ER+/HER2- . High CMP enriched epithelial-to-mesenchymal transition and angiogenesis pathways, and less cell proliferation and DNA repair gene sets. High CMP ER+/HER2- was associated with less immune cell infiltration, and cytolytic activity (P<0.001). CMP infiltration correlated with neoadjuvant chemoimmunotherapy response for both ER+/HER2- and TNBC in the ISPY-2 cohort (AUC=0.69 and 0.74, respectively). CONCLUSIONS: CMP in BC is inversely associated with cell-proliferation and brain metastasis, better response to immunotherapy and survival. This is the first to report the clinical relevance of CMP infiltration in BC.
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PURPOSE: CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER + /HER2-) BC, the most abundant subtype, remains unknown. METHODS: The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data. RESULTS: Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER + /HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/ß-Catenin, Hedgehog, and Notch signaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts. CONCLUSION: CD133-high ER + /HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.
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PURPOSE: While comprehensive research exists on the mutation of the DNA repair gene BRCA1, limited information is available regarding the clinical significance of BRCA1 gene expression. Given that cancer cell proliferation is aggrevated by DNA repair, we hypothesized that high BRCA1 gene expression breast cancer (BC) might be linked with aggressive tumor biology and poor clinical outcomes. METHODS: The cohorts: The Cancer Genome Atlas (TCGA, n = 1069), METABRIC (n = 1903), and SCAN-B (n = 3273) were utilzed to obtain data of 6245 BC patients. RESULTS: BC patients without BRCA1 mutation exhibited higher BRCA1 expression, which was associated with DNA repair functionality. However, no such correlation was observed with BRCA2 expression. The association of high BRCA1 expression with cancer cell proliferation was evidenced by significant enrichment of cell proliferation-related gene sets, higher histological grade, and proliferation score. Furthermore, increased levels of homologous recombination deficiency, intratumoral heterogeneity, and altered fractions were associated with high BRCA1 expression. Moreover, BC with high BRCA1 expression exhibited reduced infiltration of dendritic cells and CD8 T-cells, while showing increased infiltration of Th1 cells. Surprisingly, BRCA1 expression was not associated with the survival of BC irrespective of the subtypes. Conversely, BC with low BRCA1 expression enriched cancer aggravating pathway gene sets, such as Cancer Stem Cell-related signaling (NOTCH and HEDGEHOG), Angiogenesis, Epithelial-Mesenchymal Transition, Inflammatory Response, and TGF-beta signaling. CONCLUSION: Despite being linked to heightened proliferation of cancer cells and unassertive phenotype, BRCA1 expression did not show any association with survival in BC.
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BACKGROUND: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate and an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates will have better survival outcomes than patients living in colder climates. METHODS: A retrospective population-based analysis was conducted on 270,496 stage I-III breast cancer patients, who were retrieved from the Surveillance, Epidemiology and End Results (SEER) over the period from 1996 to 2017. The average annual temperature (AAT) was calculated based on city level data from the National Centers for Environmental Information. RESULTS: A total of 270, 496 patients were analyzed. Temperature as assessed in quartiles. After adjusting for potential confounders, patients who lived in the 3rd and 4th quartile temperature regions with AAT 56.7-62.5°F (3rd quartile) and > 62.5°F (4th quartile) had a 7% increase in the OS compared to patients living at AAT < 48.5°F (1st quartile) (HR 0.93, 95% CI 0.90-0.95 and HR 0.93, 95% CI 0.91-0.96, respectively). For DSS, When comparing AAT quartiles, patients living with AAT in the range of 56.7-62.5°F and > 62.5°F demonstrated a 7% increase each in DSS after adjustment (HR 0.93, 95% CI 0.90-0.96 and HR 0.93, 95% CI 0.90-0.96). CONCLUSIONS: Higher environmental temperatures are associated with significantly better OS and DSS in breast cancer patients. Future research is warranted to confirm this observation using large datasets to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.
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Neoplasias da Mama , Programa de SEER , Temperatura , Humanos , Feminino , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Adulto , Estadiamento de Neoplasias , Estados Unidos/epidemiologia , PrognósticoRESUMO
INTRODUCTION: RAD51 is a pivotal DNA repair gene managing double-stranded DNA break recognition and repair. RAD51 high expression was associated with adverse outcomes in other cancer types. This study aims to investigate the tumor microenvironment and immune landscape in the RAD51 high-expressed Hepatocellular Carcinoma (HCCs). METHODS: A total of 467 patients from two large independent cohorts with clinical and transcriptomic data were obtained. The cohort was dichotomized based on the median RAD51 gene expression. xCell and Gene Set Enrichment Analysis (GSEA) were used. RESULTS: RAD51 high-expressed HCCs were associated with worse recurrence-free, progression-free, disease-specific, and overall survival (all P < 0.05). While RAD51 high-expressed HCCs were associated with intratumoral heterogeneity, homologous recombination deficiency, and fraction altered scores, mutation or neoantigens were not increased in this group. xCell analysis demonstrated inconsistent immune cell infiltration between two cohorts. Cytolytic activity as well as GSEA with immune-related gene sets also demonstrated inconsistent results between two cohorts as well. On the other hand, RAD51 expression was significantly increased in higher-grade tumors, larger tumors, and higher clinical stages. RAD51 high-expressed HCCs were found to have elevated proliferation score. Furthermore, GSEA exhibited significant enrichment of all the cell proliferation-related gene sets in the Hallmark collection, including E2F targets, G2M checkpoint, Mitotic spindle, MYC targets, and MTORC1 signaling consistently in both cohorts (all false discovery rate < 0.25). CONCLUSIONS: RAD51 high-expressed HCCs were associated with worse survival and with increased cell proliferation and were not necessarily associated with immune infiltration or inflammation.
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Tumor-infiltrating lymphocytes are a general term for lymphocytes or immune cells infiltrating the tumor microenvironment. Numerous studies have demonstrated tumor-infiltrating lymphocytes to be robust prognostic and predictive biomarkers in breast cancer. Recently, immune checkpoint inhibitors, which directly target tumor-infiltrating lymphocytes, have become part of standard of care treatment for triple-negative breast cancer. Surprisingly, tumor-infiltrating lymphocytes quantified by conventional methods do not predict response to immune checkpoint inhibitors, which highlights the heterogeneity of tumor-infiltrating lymphocytes and the complexity of the immune network in the tumor microenvironment. Tumor-infiltrating lymphocytes are composed of diverse immune cell populations, including cytotoxic CD8-positive T lymphocytes, B cells and myeloid cells. Traditionally, tumor-infiltrating lymphocytes in tumor stroma have been evaluated by histology. However, the standardization of this approach is limited, necessitating the use of various novel technologies to elucidate the heterogeneity in the tumor microenvironment. This review outlines the evaluation methods for tumor-infiltrating lymphocytes from conventional pathological approaches that evaluate intratumoral and stromal tumor-infiltrating lymphocytes such as immunohistochemistry, to the more recent advancements in computer tissue imaging using artificial intelligence, flow cytometry sorting and multi-omics analyses using high-throughput assays to estimate tumor-infiltrating lymphocytes from bulk tumor using immune signatures or deconvolution tools. We also discuss higher resolution technologies that enable the analysis of tumor-infiltrating lymphocytes heterogeneity such as single-cell analysis and spatial transcriptomics. As we approach the era of personalized medicine, it is important for clinicians to understand these technologies.
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Neoplasias da Mama , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Humanos , Linfócitos do Interstício Tumoral/imunologia , Feminino , Microambiente Tumoral/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , PrognósticoRESUMO
OBJECTIVE: To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes. SUMMARY BACKGROUND DATA: Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells. METHODS: In all, 5870 breast cancer patients from TCGA, METABRIC, GSE96058, GSE25066, GSE163882, GSE123845, and GSE20271 cohorts were analyzed and validated. RESULTS: The intratumoral TIL score was established by the sum of all types of lymphocytes using the xCell algorithm. This score was the highest in triple-negative breast cancer (TNBC) and the lowest in the ER-positive/HER2-negative subtype. It correlated with cytolytic activity and infiltrations of dendritic cells, macrophages, and monocytes, and uniformly enriched immune-related gene sets regardless of subtype. Intratumoral TIL-high tumors correlated with higher mutation rates and significant cell proliferation on biological, pathological, and molecular analyses only in the ER-positive/HER2-negative subtype. It was significantly associated with pathological complete response after anthracycline- and taxane-based neoadjuvant chemotherapy in about half of the cohorts, regardless of the subtype. Intratumoral TIL-high tumors correlated with better overall survival in HER2-positive and TNBC subtypes consistently in 3 cohorts. CONCLUSIONS: Intratumoral TILs estimated by transcriptome computation were associated with increased immune response and cell proliferation in ER-positive/HER2-negative and better survival in HER2-positive and TNBC subtypes, but not always with pathological complete response after neoadjuvant chemotherapy.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Intervalo Livre de Doença , Linfócitos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Terapia Neoadjuvante , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: Pancreatic cancer (PC) has an extremely high mortality rate, where obstructive jaundice due to cholestasis is a classic symptom. Conjugated bile acids (CBAs) such as taurocholic acid (TCA) have been reported to activate both the ERK1/2 and AKT signaling pathways via S1P receptor 2 (S1PR2) and promote growth of cholangiocarcinoma. Thus, we hypothesize that CBAs, which accumulate in cholestasis, accelerate PC progression via S1PR2. METHODS: Murine Panc02-luc and human AsPC-1, MIA PaCa2, and BxPC-3 cells were treated with TCA, S1PR2 agonist CYM5520, S1PR2 antagonist JTE-013, sphingosine-1-phosphate (S1P), and functional S1P receptor antagonist (except S1PR2) FTY720. Bile duct ligation (BDL) was performed on liver implantation or intraperitoneal injection of Panc02-luc cells. RESULTS: Panc02-luc and AsPC-1 cells predominantly expressed S1PR2, and their growth and migration were stimulated by TCA or CYM5520 in dose-dependent manner, which was blocked by JTE-013. This finding was not seen in PC cell lines expressing other S1P receptors than S1PR2. Panc02-luc growth stimulation by S1P was not blocked by FTY720. BDL significantly increased PC liver metastasis compared with sham. PC peritoneal carcinomatosis was significantly worsened by BDL, confirmed by number of nodules, tumor weight, bioluminescence, Ki-67 stain, ascites, and worse survival compared with sham. CYM5520 significantly worsened PC carcinomatosis, whereas treatment with anti-S1P antibody or FTY720 also worsened progression. CONCLUSIONS: CBAs accelerated growth of S1PR2 predominant PC both in vitro and in vivo. This finding implicates S1PR2 as a potential therapeutic target in metastatic S1PR2 predominant pancreatic cancer.
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Neoplasias dos Ductos Biliares , Colestase , Neoplasias Hepáticas , Neoplasias Pancreáticas , Camundongos , Humanos , Animais , Receptores de Esfingosina-1-Fosfato , Receptores de Lisoesfingolipídeo/metabolismo , Cloridrato de Fingolimode , Colestase/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Esteroides , Ácidos e Sais Biliares , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/patologiaRESUMO
Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.
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Neoplasias da Mama , Receptores de Ácidos Lisofosfatídicos , Humanos , Feminino , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Neoplasias da Mama/genética , Microambiente Tumoral/genética , Células Endoteliais/metabolismo , Transdução de Sinais , Lisofosfolipídeos/metabolismoRESUMO
BACKGROUND: Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Efficacious treatment options are scarce. We investigated the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases. METHODS: We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Patients aged 18 years or older who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2, received pyrotinib 400 mg orally once daily, and capecitabine 1000 mg/m2 orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed intracranial objective response rate by investigator assessment according to the Response Evaluation Criteria In Solid Tumours (version 1.1). Activity and safety were analysed in patients with at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT03691051. FINDINGS: Between Jan 29, 2019, and July 10, 2020, we enrolled 78 women: 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab. Median follow-up duration was 15·7 months (IQR 9·7-19·0). The intracranial objective response rate was 74·6% (95% CI 61·6-85·0; 44 of 59 patients) in cohort A and 42·1% (20·3-66·5; eight of 19 patients) in cohort B. The most common grade 3 or worse treatment-emergent adverse event was diarrhoea (14 [24%] in cohort A and four [21%] in cohort B). Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: To our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial. FUNDING: National Cancer Centre Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Neoplasias Encefálicas , Neoplasias da Mama , Acrilamidas , Aminoquinolinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Capecitabina , Feminino , Humanos , Masculino , Estudos Prospectivos , Receptor ErbB-2/metabolismoRESUMO
PURPOSE: Platelet-derived growth factor B (PDGFB) is known to play essential roles in angiogenesis and lymphangiogenesis during development, and tumor growth and vessel stabilization in experimental models. However, whether these findings could be translated to breast cancer patients remains unclear. We hypothesized that PDGFB gene expression is associated with angiogenesis, cell proliferation, and clinical outcomes in breast cancer patients. METHODS: A total of 7635 primary breast cancer patients with full transcriptome and clinical data available from 13 independent cohorts were analyzed using in silico approach. The median value was used to divide each cohort into high and low PDGFB expression groups. RESULTS: High PDGFB gene expression was associated with increased expression of angiogenesis-related genes, higher amount of vascular cell infiltrations, and with enrichment of angiogenesis gene set, lymphangiogenesis-related gene expressions, lymphangiogenesis-related cell infiltrations, and enrichmentof lymphangiogenesis gene set in GSE96058 and validated by TCGA cohorts; however, not with lymphatic metastasis. PDGFB expression was neither associated with cell proliferation as assessed by Ki67 expression nor with Nottingham histological grade, or response to neoadjuvant chemotherapy. We found that PDGFB was most extensively expressed by endothelial and perivascular-like cells in the tumor microenvironment, and minimally by cancer cells consistently in two single-cell sequence cohorts. High PDGFB expression enriched TGFß, epithelial-mesenchymal transition, hypoxia, and cancer stem cell-associated pathways. However, no association with distant metastasis was observed. Disease-specific and disease-free survival were worse in the high PDGFB expression group consistently in TCGA and METABRIC cohorts. CONCLUSION: PDGFB is predominantly expressed in endothelial cells and is associated with angiogenesis and lymphangiogenesis, but not with cellular proliferation or metastasis in breast cancer.
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Neoplasias da Mama , Linfangiogênese , Neoplasias da Mama/patologia , Células Endoteliais/metabolismo , Feminino , Genes sis , Humanos , Linfangiogênese/genética , Neovascularização Patológica/genética , Proteínas Proto-Oncogênicas c-sis/genética , Microambiente TumoralRESUMO
PURPOSE: Although the DNA repair mechanism is important in preventing carcinogenesis, its activation in established cancer cells may support their proliferation and aggravate cancer progression. RAD51 cooperates with BRCA2 and is essential in the homologous recombination of DNA repair. To this end, we hypothesized that RAD51 gene expression is associated with cancer cell proliferation and poor prognosis of breast cancer (BC) patients. METHODS: A total of 8515 primary BC patients with transcriptome and clinical data from 17 independent cohorts were analyzed. The median value was used to divide each cohort into high and low RAD51 expression groups. RESULTS: High RAD51 expression enriched the DNA repair gene set and was correlated with DNA repair-related genes. Nottingham histological grade, Ki67 expression and cell proliferation-related gene sets (E2F Targets, G2M Checkpoint and Myc Targets) were all significantly associated with the high RAD51 BC group. RAD51 expression was positively correlated with Homologous Recombination Deficiency, as well as both mutational burden and neoantigens that accompanied a higher infiltration of immune cells. Primary BC with lymph node metastases was associated with high expression of RAD51 in two cohorts. There was no strong correlation between RAD51 expression and drug sensitivity in cell lines, and RAD51 expression was lower after the neoadjuvant chemotherapy compared to before the treatment. High RAD51 BC was associated with poor prognosis consistently in three independent cohorts. CONCLUSION: RAD51 gene expression is associated with aggressive cancer biology, cancer cell proliferation, and poor survival in breast cancer.
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Neoplasias da Mama , Biologia , Neoplasias da Mama/patologia , Reparo do DNA/genética , Feminino , Expressão Gênica , Genes BRCA2 , Humanos , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismoRESUMO
PURPOSE: Sentinel lymph node biopsy is omitted in older women (≥ 70 years old) with clinical lymph node (LN)-negative hormone receptor-positive breast cancer as it does not influence adjuvant treatment decision-making. However, older women are heterogeneous in frailty while the chance of recurrence increase with improving longevity. Therefore, a biomarker that identifies LN metastasis may facilitate treatment decision-making. RUFY3 is associated with cancer progression. We evaluated RUFY3 expression level as a biomarker for LN-positive breast cancer in older women. METHODS: Clinical and transcriptomic data of breast cancer patients were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1903) and The Cancer Genome Atlas (TCGA, n = 1046) Pan-cancer study cohorts. RESULTS: A total of 510 (METABRIC) and 211 (TCGA) older women were identified. LN-positive breast cancer, which represented 51.4% (METABRIC) and 48.4% (TCGA), demonstrated worse disease-free, disease-specific, and overall survival. RUFY3 levels were significantly lower in LN-positive tumors regardless of age. The area under the curve for the receiver operator characteristic (AUC-ROC) curves showed RUFY3-predicted LN metastasis. Low RUFY3 enriched oxidative phosphorylation, DNA repair, MYC targets, unfolded protein response, and mtorc1 signaling gene sets, was associated with T helper type 1 cell infiltration, and with intratumor heterogeneity and fraction altered. Low RUFY3 expression was associated with LN-positive breast cancer and with worse disease-specific survival among older women. CONCLUSION: Older women with breast cancers who had low expression level of RUFY3 were more frequently diagnosed with LN-positive tumors, which translated into worse prognosis.
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Neoplasias da Mama , Idoso , Axila , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Proteínas do Citoesqueleto , Feminino , Humanos , Excisão de Linfonodo , Linfonodos , Metástase Linfática , Biópsia de Linfonodo SentinelaRESUMO
PURPOSE: Reactive oxygen species (ROS) are oxygen-containing molecules that have high reactivity and play roles in protection or harm the cancer cells. We aimed to clarify the clinical relevance of ROS in breast cancer (BC) tumor microenvironment (TME). We hypothesized that it is associated with worse BC patient outcomes. METHODS: ROS score was generated by Gene Set Variation Analysis of Hallmark ROS pathway gene set and a total of 6245 BC patients were analyzed. RESULTS: High ROS BC significantly enriched cell proliferation-related gene sets (MYC targets v1 and v2, G2M checkpoint, E2F targets), pro-cancer-related gene sets (DNA repair, unfolded protein response, MTORC1 signaling, PI3K/AKT/MTOR signaling, glycolysis, and oxidative phosphorylation), immune-related gene sets (inflammatory response, allograft rejection, interferon-α and γ responses, complement, and IL6/JAK/STAT3 signaling), and infiltrated immune cells (CD4+ memory and CD8+ T cells, Th1 and Th2, dendritic cells, Tregs, M1 and M2 macrophages) and B cells, as well as elevated cytolytic activity consistently in both METABRIC and GSE96058 cohorts. Cancer cells were the major source of ROS in BC TME of single-cell sequence (GSE75688) cohort. High ROS was associated with intratumor heterogeneity, homologous recombination defects, mutation rates, and neoantigens, and with clinical aggressiveness in AJCC stage, Nottingham grade and Ki67 expression, as well as worse overall survival in both GSE96058 and METABRIC, and with worse disease-specific survival in METABRIC. CONCLUSION: Abundant ROS in BC patients is associated with abundant mutations, aggressive cancer biology, immune response, and worse survival.
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Neoplasias da Mama , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Imunidade , Fosfatidilinositol 3-Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/genéticaRESUMO
PURPOSE: To examine the association between race and clinical outcomes (pathological complete response [pCR]; recurrence-free survival [RFS], and overall survival [OS]) in patients diagnosed with triple-negative (TNBC) or HER2-positive breast cancer treated with neoadjuvant chemotherapy (NAC). METHODS: Patients who self-identified as non-Hispanic white (NHW) or non-Hispanic Black (NHB) and were diagnosed with Stage I-III TNBC (n = 171 including 124 NHW and 47 NHB) and HER2-positive (n = 161 including 136 NHW and 25 NHB) breast cancer who received NAC from 2000 to 2018 at Roswell Park Comprehensive Cancer Center were included. Associations of race with pCR and survival outcomes were evaluated using logistic and Cox regression models, respectively. RESULTS: There was no statistically significant difference in pCR between NHB and NHW patients with TNBC (31.9 vs 29.8%; OR: 1.11, 95% CI 0.54-2.29) or HER2-positive breast cancer (36.0 vs 39.7%; OR: 0.87, 95% CI 0.36-3.11). After controlling for potential confounders, including age, stage, treatment regimens, insurance status, and comorbidities, no statistically significant difference in OS or RFS was observed between NHB and NHW patients within either subtype. CONCLUSION: TNBC or HER2-positive breast cancer patients treated at a single academic center in Buffalo, NY, showed similar outcomes independent of patients' race. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography, and clinical outcomes are warranted.
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Neoplasias da Mama , Terapia Neoadjuvante , Negro ou Afro-Americano/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Etnicidade , Feminino , Humanos , Fatores Raciais , Estados UnidosRESUMO
BACKGROUND: Mechanically gated PIEZO channels lead to an influx of cations, activation of additional Ca2+ channels, and cell depolarization. This study aimed to investigate PIEZO2's role in breast cancer. METHODS: The clinical relevance of PIEZO2 expression in breast cancer patient was analyzed in a publicly available dataset. Utilizing PIEZO2 overexpressed breast cancer cells, and in vitro and in vivo experiments were conducted. RESULTS: High expression of PIEZO2 was correlated with a worse survival in triple-negative breast cancer (TNBC) but not in other subtypes. Increased PEIZO2 channel function was confirmed in PIEZO2 overexpressed cells after mechanical stimulation. PIEZO2 overexpressed cells showed increased motility and invasive phenotypes as well as higher expression of SNAIL and Vimentin and lower expression of E-cadherin in TNBC cells. Correspondingly, high expression of PIEZO2 was correlated with the increased expression of epithelial-mesenchymal transition (EMT)-related genes in a TNBC patient. Activated Akt signaling was observed in PIEZO2 overexpressed TNBC cells. PIEZO2 overexpressed MDA-MB-231 cells formed a significantly higher number of lung metastases after orthotopic implantation. CONCLUSION: PIEZO2 activation led to enhanced SNAIL stabilization through Akt activation. It enhanced Vimentin and repressed E-cadherin transcription, resulting in increased metastatic potential and poor clinical outcomes in TNBC patients.
Assuntos
Neoplasias de Mama Triplo Negativas , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Canais Iônicos/genética , Fenótipo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Vimentina/genética , Vimentina/metabolismoRESUMO
BACKGROUND: Mutations of BRCA genes are the most studied in breast cancer, but the clinical relevance of BRCA2 gene expression has been less well studied. Given that BRCA2 is a DNA repair gene, we hypothesized that high BRCA2 expression is associated with highly proliferative and aggressive biology in breast cancer. MATERIALS AND METHODS: A total of 4342 breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA, n = 1069) as the testing cohort and Gene Expression Omnibus (GEO) dataset GSE96058 (n = 3273) as a validation cohort. RESULTS: There was no relationship between BRCA2 mutation and BRCA2 gene expression. BRCA2 high expression breast cancer was associated with higher Nottingham grade (p < 0.001), with high proliferation (MKI-67, p < 0.001), and with higher intratumor heterogeneity, homologous recombination deficiency, mutation rate, fraction altered, and neoantigens (all p < 0.001). BRCA2 high expression was associated with E2F1, RB1, PALB2, and PARP, as well as cell proliferation-related gene sets, E2F targets, G2M checkpoints, and mitotic spindle, and with less ESR1 and ER response early and late gene sets. They were associated with significantly reduced number of stroma cells and with high infiltration of both favorable and unfavorable immune cells. BRCA2 high expression significantly correlated with response to olaparib, a PARP inhibitor, and inversely with cyclophosphamide in ER-positive/HER2-negative tumors, but not in TNBC. CONCLUSIONS: BRCA2 high gene expression was associated with highly proliferative and aggressive breast cancer that was highly immunogenic with better response to PARP inhibitors in ER-positive patients. BRCA2 gene expression may become a candidate marker for aggressive biology and to tailor specific treatment strategies in the future.
Assuntos
Proteína BRCA2 , Neoplasias da Mama , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Expressão Gênica , Genes BRCA2 , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine-1-phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia-responsive master transcription factors hypoxia-inducible factor (HIF)-1α/2α, and their functions in breast cancer, with a focus on triple-negative breast cancer (TNBC). We have shown SphK2 is associated with HIF-1α in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor (VEGF), where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF-1α. SphK2, and HIF-1α expression levels are elevated in metastatic estrogen receptor-positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K-145, that nuclear S1P, histone acetylation, HIF-1α expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF-1α/2α functions associated with breast cancer progression, and may provide potential therapeutic targets.
Assuntos
Núcleo Celular/metabolismo , Lisofosfolipídeos/metabolismo , Receptor A2B de Adenosina/metabolismo , Esfingosina/análogos & derivados , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Acetilação , Adenosina/metabolismo , Animais , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Ensaio de Imunoadsorção Enzimática , Epigênese Genética/genética , Epigênese Genética/fisiologia , Feminino , Humanos , Immunoblotting , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Receptor A2B de Adenosina/genética , Esfingosina/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Oligometastasis, the presence of a small number of resectable metastatic tumors, usually has favorable outcomes. Here we examined whether the novel oligometastatic score (OLGS), which divides the number of colorectal liver metastases (CRLMs) by the time from colorectal resection to liver recurrence, better predicts CRLM patient survival than the commonly used clinical risk score. METHODS: A total of 143 patients who underwent curative hepatectomy for CRLMs between 2007 and 2018 were analyzed. We investigated their clinical characteristics and outcomes using OLGS. RESULTS: Of the 143 CRLM patients, 70 had synchronous CRLMs and 73 had metachronous CRLMs. Patients with metachronous CRLMs were divided into OLGS-low (n = 59) and OLGS-high (n = 14) subgroups. The 5-year overall survival (OS) rates after hepatectomy differed significantly between the subgroups (p < .001). In the multivariate Cox model, a high OLGS was an independent predictor of 5-year OS (p < .001), and the hazard ratio (HR) of the OLGS-high group (HR = 7.171) was higher than that of the high clinical risk score group (HR = 4.337). CONCLUSION: The OLGS, a simple and handy scoring system, better predicts the 5-year OS of patients with CRLMs after hepatectomy and warrants prospective validation.