circUSP42 Is Downregulated in Triple-Negative Breast Cancer and Associated With Poor Prognosis

We previously showed that microRNA-182 (miR-182) might promote cell proliferation and migration in triple-negative breast cancer (TNBC). This study aimed to investigate circular RNAs (circRNAs) that interact with miR-182 and play important roles in TNBC. Thirty patients with TNBC were enrolled. One pair of tumor and adjacent tissue samples (control) were submitted for circRNA sequencing to establish the expression profile of circRNAs. Concomitantly, circRNAs aberrantly expressed between TNBC and control groups were identified, and these differentially expressed circRNAs (DEcircRNAs) were subjected to Gene Ontology and KEGG pathway enrichment analyses, as well as prediction of interactions with miRNAs. The expression levels of 5 circRNAs interacting with miR-182 were validated using qRT-PCR. Associations between the expression of circUSP42 and clinicopathological features and prognosis were evaluated. A total of 825 upregulated and 1127 downregulated DEcircRNAs were identified between tumor and control groups. Upregulated DEcircRNAs were significantly involved in proteoglycans in cancer, and endocytosis. Downregulated DEcircRNAs were involved in the pathway of resistance to EGFR tyrosine kinase inhibitors. Prediction of circRNA-miRNA interactions showed that hsa_circ_0002032, chr6:131973682-132047340+, hsa_circ_0005982, hsa_circ_0007823 (circUSP42), and hsa_circ_0001777 might act as miRNA sponges for miR-182. qRT-PCR showed consistent results with circRNA sequencing data ( P < 0.05). Downregulation of circUSP42 was significantly associated with lymph node metastasis ( P = 0.005) and advanced clinical stage ( P = 0.032). Furthermore, Kaplan-Meier plots showed that low expression of circUSP42 was closely associated with poor outcome (log-rank test, P < 0.001). Our data suggested that dysregulation of circUSP42 might contribute to the development and progression of TNBC.

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GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002383 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002383

Author(s):

Jin-Li Wei ◽

Si-Yu Wu ◽

Yun-Song Yang ◽

Yi Xiao ◽

Xi Jin ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Taxonomy ◽

Underlying Mechanism ◽

Metabolic Reprogramming ◽

Sequencing Data ◽

Aryl Hydrocarbon

PurposeRegulatory 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 designUsing 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.ResultsWe 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.ConclusionsTumor-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.

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CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway

Molecular Cancer ◽

10.1186/s12943-021-01332-8 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Lei Wang ◽

Yehui Zhou ◽

Liang Jiang ◽

Linlin Lu ◽

Tiantian Dai ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Luciferase Reporter ◽

Akt Pathway ◽

Circular Rnas ◽

Chemotherapeutic Resistance ◽

Repressive Effect

Abstract Background Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs). Methods TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC. Results CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor. Conclusions CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.

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CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer

Molecular Cancer ◽

10.1186/s12943-021-01321-x ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Ya Fan ◽

Jia Wang ◽

Wen Jin ◽

Yifei Sun ◽

Yuemei Xu ◽

...

Keyword(s):

Breast Cancer ◽

Rna Sequencing ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Proteasomal Degradation ◽

Circular Rnas ◽

Mesenchymal Transition

Abstract Background E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. Recent studies characterized circular RNAs (circRNAs) playing an regulatory role as miRNA sponge in tumor progression, presenting a new viewpoint for the post-transcriptional regulation of cancer-related genes. Methods Examination of the expression of HRD1 protein and mRNA was implemented using public microarray/RNA-sequencing datasets and breast cancer tissues/cell lines. Based on public RNA-sequencing results, online databases and enrichment/clustering analyses were used to predict the specific combinations of circRNA/miRNA that potentially govern HRD1 expression. Gain-of-function and rescue experiments in vitro and in vivo were executed to evaluate the suppressive effects of circNR3C2 on breast cancer progression through HRD1-mediated proteasomal degradation of Vimentin, which was identified using immunoblotting, immunoprecipitation, and in vitro ubiquitination assays. Results HRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) against other subtypes and has an inverse correlation with Vimentin, inhibiting the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) process of breast cancer cells via inducing polyubiquitination-mediated proteasomal degradation of Vimentin. CircNR3C2 (hsa_circ_0071127) is also remarkably downregulated in TNBC, negatively correlated with the distant metastasis and lethality of invasive breast carcinoma. Overexpressing circNR3C2 in vitro and in vivo leads to a crucial enhancement of the tumor-suppressive effects of HRD1 through sponging miR-513a-3p. Conclusions Collectively, we elucidated a bona fide circNR3C2/miR-513a-3p/HRD1/Vimentin axis that negatively regulates the metastasis of TNBC, suggesting that circNR3C2 and HRD1 can act as potential prognostic biomarkers. Our study may facilitate the development of therapeutic agents targeting circNR3C2 and HRD1 for patients with aggressive breast cancer.

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Abstract 2835: Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition

10.1158/1538-7445.am2016-2835 ◽

2016 ◽

Cited By ~ 1

Author(s):

Joyoti Dey ◽

Joseph Casalini ◽

Sally Ditzler ◽

Matt Biery ◽

Angela Merrell ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Clinical Stage ◽

Proteasome Inhibition ◽

Cdk Inhibitor ◽

Breast Cancer Xenografts

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Immunohistological Expression of SOX-10 in Triple-Negative Breast Cancer: A Descriptive Analysis of 113 Samples

International Journal of Molecular Sciences ◽

10.3390/ijms21176407 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6407 ◽

Cited By ~ 1

Author(s):

Katharina Kriegsmann ◽

Christa Flechtenmacher ◽

Jörg Heil ◽

Jörg Kriegsmann ◽

Gunhild Mechtersheimer ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Descriptive Analysis ◽

Biological Significance ◽

Genetic Alterations ◽

Prognostic Impact ◽

Cancer Genes ◽

Sequencing Data ◽

Disease Free

Background: SRY-related HMG-box 10 (SOX-10) is commonly expressed in triple negative breast cancer (TNBC). However, data on the biological significance of SOX-10 expression is limited. Therefore, we investigated immunhistological SOX-10 expression in TNBC and correlated the results with genetic alterations and clinical data. Methods: A tissue microarray including 113 TNBC cases was stained by SOX-10. Immunohistological data of AR, BCL2, CD117, p53 and Vimentin was available from a previous study. Semiconductor-based panel sequencing data including commonly altered breast cancer genes was also available from a previous investigation. SOX-10 expression was correlated with clinicopathological, immunohistochemical and genetic data. Results: SOX-10 was significantly associated with CD117 and Vimentin, but not with AR expression. An association of SOX-10 with BCL2, EGFR or p53 staining was not observed. SOX-10-positive tumors harbored more often TP53 mutations but less frequent mutations of PIK3CA or alterations of the PIK3K pathway. SOX-10 expression had no prognostic impact either on disease-free, distant disease-free, or overall survival. Conclusions: While there might be a value of SOX-10 as a differential diagnostic marker to identify metastases of TNBC, its biological role remains to be investigated.

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Triple negative breast cancer: 5-year results of combined treatment

Acta medica Lituanica ◽

10.6001/actamedica.v20i4.2816 ◽

2014 ◽

Vol 20 (4) ◽

pp. 191-198

Author(s):

Valerijus Ostapenko ◽

Teresė Pipirienė Želvienė ◽

Giedrė Smailytė ◽

Andrej Ostapenko ◽

Raimundas Meškauskas

Keyword(s):

Breast Cancer ◽

Retrospective Analysis ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Option ◽

Combined Treatment ◽

Disease Free Survival ◽

Rank Test ◽

Biological Behaviour ◽

Metastatic Setting

Background. Breast cancer is the most common female cancer worldwide. It is a heterogeneous disease with regard to biological behaviour, responses to treatment and prognosis. The term “triple negative breast cancer” (TNBC), namely, refers to the immunohistochemical classification of breast tumours lacking ER, PgR, and HER2 protein expression. TNBC does not respond to endocrine therapy and chemotherapy remains the main systemic therapeutic option in the adjuvant and metastatic setting of TNBC. The aim of this study was a retrospective analysis of the results of combined treatment for TNBC. Patient and methods. In our retrospective analysis, we analized 431 patients with TNBC treated with combination therapy from March 2005 until December 2009 at the Institute of Oncology, Vilnius University. 52.20% of the whole group of patients were women older than 50 years. Stage I was diagnosed in 23.9%, stage II in 49.65%, stage III in 22.74%, stage IV in 3.71% of cases. According to pathological types of the tumour ductal invasive carcinoma was diagnosed in 376 patients (87.24%) and tumour grade G3 was determined in 330 patients (76.57%). All 431 patients underwent surgical treatment, 239 patients had chemotherapy (55.45%). The disease-free survival and overall survival were estimated by the Kaplan-Meier method. The Log-rank test was used for survival comparison between the groups. P

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Pathologic response to neoadjuvant therapy with nabpaclitaxel plus carboplatin followed by anthracycline regimen in triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e12117 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e12117-e12117

Author(s):

Juan David Cardenas ◽

Carmen Esteban ◽

Iciar Garcia Carbonero ◽

Adriana Rosero ◽

Katherin Martinez Barroso ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Hormone Receptors ◽

Triple Negative ◽

Clinical Stage ◽

Pathologic Complete Response ◽

Neoadjuvant Treatment ◽

Conservative Surgery ◽

Stage Ii ◽

Hematologic Toxicity

e12117 Background: Triple-negative breast cancer (TNBC) remains a poor prognosis subtype of breast cancer (BC). We are lacking of definitive effective combinations in this tumor. So, it is warranted to explore new combinations. Neo-adjuvant setting is one of the most effective scenarios to explore a treatment efficacy. We aimed to evaluate efficacy of Nab-paclitaxel plus Carboplatin followed byanthracycline regimen by pathologic complete response (pCR: no disease in breast and axilla) in women with TNBC. Secondary endpoints were toxicity profile and breast conserving surgery. Methods: Women with stage II or III disease were included. Hormone receptors and HER2 negativity was confirmed by immunohistochemistry and/or FISH. Patients received Nab-paclitaxel 125 mg/m2 plus Carboplatin AUC 2 intravenously on days 1, 8 every 21 for four cycles followed by Epirubicin 90 mg/m2 and Cyclophosphamide 600 mg/m2 intravenously every 2 weeks for 4 cycles and subsequent surgery. Breast Magnetic Resonance was done in all cases at diagnosis and before surgery. We obtained informed consent from all patients. Results: Thirty-two patients with confirmed clinical stage II (56.3%) or III (43.7%) TNBC were treatedbetween January 2015 and February 2019. The median age of the patients was 53.1 years (30.3-77.6 years). The average of received chemotherapy was 12 doses (7-14). The mean dose of nab-paclitaxel plus carboplatin was 8 doses. All patients received surgery with or without radiotherapy. There was only one case (3.1%) of progression during neoadjuvant treatment. The rate of pCR was 50% (16) in breast and axilla, partial response 43.8% (14) and stable disease 3.1% (1). Conservative surgery was performed in 50% of patients (16). The 3/4 grade toxicities were asthenia 3.1% (1), nausea/vomiting 6.3% (2), thrombocytopenia 6.3% (2), leukopenia 6.3% (2), neutropenia 40.6% (13), febrile neutropenia 6.3% (2), diarrhea 3.1% (1), allergy 3.1% (1), peripheral neurotoxicity 3.1% (1). After a median follow-up of 18.3 months (5.0–41.9) 93.8% (30) of patients are alive. Two patients (6.3%) had early local relapse and distant relapse, respectively, and are deceased due to progression disease. Conclusions: Nab-paclitaxel plus carboplatin followed by anthracycline regimencombination as neoadjuvant treatment in TNBC achieved an encouraging rate of pCR, allowing conservative surgery in half of our patients. Toxicities were not severe in most patients and hematologic toxicity was manageable with G-CSF.

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Pathogenic variants inBRCA1/2genes among patientswith triple-negative breast cancer: a case series

Mastology ◽

10.29289/2594539420210032 ◽

2021 ◽

Vol 31 ◽

Author(s):

Rafael Everton Assunção Ribeiro da Costa ◽

Fergus Tomás Rocha de Oliveira ◽

Ana Lúcia Nascimento Araújo ◽

Sabas Carlos Vieira

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Residual Disease ◽

Molecular Subtype ◽

Clinical Stage ◽

Case Series ◽

Neoplastic Disease ◽

Ki 67 ◽

Pathogenic Variants

Triple-negative breast cancer (TNBC) is an uncommon molecular subtype (representing 15%–20% of breast cancers) characterized by the non-expression of estrogen receptor, progesterone receptor, and human epidermal growth receptor factor 2. More aggressive and lethal, TNBC is often associated with pathogenic variants in BRCA1/2 genes. This study aimed to describe a series of seven cases of patients with TNBC and pathogenic variants in BRCA1/2 genes. All patients were female and under 50 years of age at diagnosis. Four of them presented a family history of breast cancer and/or other neoplasms. The predominant clinical stage was IIB, and the main anatomopathological stage was pT2pN0M0. The mean tumor size in the series was 2.5 cm (1.0 to 3.2 cm). Ki-67 was > 30% in all patients. Three cases (43%) had pathological complete response, and only one presented extensive residual disease after neoadjuvant chemotherapy. Six patients showed pathogenic variants in BRCA1 (86%) and one in BRCA2+ (14%). After a mean follow-up of 38 months (19 to 68 months), five patients were alive and without neoplastic disease, and two progressed to metastasis.

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Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.682021 ◽

2021 ◽

Vol 11 ◽

Author(s):

Meng-Yuan Wang ◽

Man Huang ◽

Chao-Yi Wang ◽

Xiao-Ying Tang ◽

Jian-Gen Wang ◽

...

Keyword(s):

Breast Cancer ◽

Rna Sequencing ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Fusion Transcript ◽

Sequencing Data ◽

Chromosome 11 ◽

Fusion Transcripts ◽

Tumor Tissues ◽

Fusion Type

BackgroundTriple-negative breast cancer (TNBC) is a highly aggressive cancer with poor prognosis. The lack of effective targeted therapies for TNBC remains a profound clinical challenge. Fusion transcripts play critical roles in carcinogenesis and serve as valuable diagnostic and therapeutic targets in cancer. The present study aimed to identify novel fusion transcripts in TNBC.MethodsWe analyzed the RNA sequencing data of 360 TNBC samples to identify and filter fusion candidates through SOAPfuse and ChimeraScan analysis. The characteristics, including recurrence, fusion type, chromosomal localization, TNBC subgroup distribution, and clinicopathological correlations, were analyzed in all candidates. Furthermore, we selected the promising fusion transcript and predicted its fusion type and protein coding capacity.ResultsUsing the RNA sequencing data, we identified 189 fusion transcripts in TNBC, among which 22 were recurrent fusions. Compared to para-tumor tissues, TNBC tumor tissues accumulated more fusion events, especially in high-grade tumors. Interestingly, these events were enriched at specific chromosomal loci, and the distribution pattern varied in different TNBC subtypes. The vast majority of fusion partners were discovered on chromosomes 1p, 11q, 19p, and 19q. Besides, fusion events mainly clustered on chromosome 11 in the immunomodulatory subtype and chromosome 19 in the luminal androgen receptor subtype of TNBC. Considering the tumor specificity and frameshift mutation, we selected MFGE8-HAPLN3 as a novel biomarker and further validated it in TNBC samples using PCR and Sanger sequencing. Further, we successfully identified three types of MFGE8-HAPLN3 (E6-E2, E5-E3, and E6-E3) and predicted the ORF of E6-E2, which could encode a protein of 712 amino acids, suggesting its critical role in TNBC.ConclusionsImproved bioinformatic stratification and comprehensive analysis identified the fusion transcript MFGE8-HAPLN3 as a novel biomarker with promising clinical application in the future.

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