ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

AbstractISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. The mechanism by which ISG15 achieves this however remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR) in non-interferon stimulated cells using CRISPR-knock out models for ISGylation. By regulating EGFR trafficking, ISGylation enhances EGFR recycling and sustains Akt-signalling. We further show that Akt signalling positively correlates with levels of ISG15 and its E2-ligase in basal breast cancer cohorts, confirming the link between ISGylation and Akt signalling in human tumours. Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in human breast cancers. We show that ISGylation can act as a driver of tumour progression rather than merely being a bystander.

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ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

10.1101/767533 ◽

2019 ◽

Author(s):

Alfonso Bolado-Carrancio ◽

Morwenna Muir ◽

Ailith Ewing ◽

Kenneth Macleod ◽

William Gallagher ◽

...

Keyword(s):

Egf Receptor ◽

Tumour Progression ◽

Survival Rates ◽

Breast Tumour ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Akt Activation ◽

Gdp Dissociation Inhibitor

ABSTRACTISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. However, the mechanism by which ISG15 achieves this remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR). By regulating EGFR trafficking, ISGylation sustains Akt-signalling in vitro and in vivo. Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in animal models and human breast cancers. We show that ISGylation can act as driver of tumour progression rather than merely being a marker of it.

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YAP and β-catenin co-operate to drive oncogenesis in basal breast cancer

10.1101/2020.06.05.115881 ◽

2020 ◽

Author(s):

Hazel Quinn ◽

Elle Koren ◽

Regina Vogel ◽

Oliver Popp ◽

Philipp Mertins ◽

...

Keyword(s):

Breast Cancer ◽

Target Genes ◽

Regulatory Elements ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Knock Out ◽

Proteomic Data ◽

Basal Breast Cancer ◽

Survival Gene ◽

Gene Regulatory Elements

AbstractTargeting cancer stem cells (CSCs) can serve as an effective approach toward limiting resistance to therapies and the development of metastases in many forms of cancer. While basal breast cancers encompass cells with CSC features, rational therapies remain poorly established. Here, we show that receptor tyrosine kinase Met signalling promotes the activity of the Hippo component YAP in basal breast cancer. Further analysis revealed enhanced YAP activity within the CSC population. Using both genetic and pharmaceutical approaches, we show that interfering with YAP activity delays basal cancer formation, prevents luminal to basal trans-differentiation and reduces CSC survival. Gene expression analysis of YAP knock-out mammary glands revealed a strong decrease in β-catenin target genes in basal breast cancer, suggesting that YAP is required for nuclear β-catenin activity. Mechanistically, we find that nuclear YAP interacts and overlaps with β-catenin and TEAD4 at common gene regulatory elements. Analysis of proteomic data from primary breast cancer patients identified a significant upregulation of the YAP activity signature in basal compared to other breast cancers, suggesting that YAP activity is limited to basal types. Our findings demonstrate that in basal breast cancers, β-catenin activity is dependent on YAP signalling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/β-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal (triple-negative) breast cancers.

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Postoperative Radiotherapy in N– Breast Cancer. A Retrospective Case-Control Study

Tumori Journal ◽

10.1177/030089168106700509 ◽

1981 ◽

Vol 67 (5) ◽

pp. 443-445 ◽

Cited By ~ 1

Author(s):

Mario Cappellini ◽

Stefano Ciatto ◽

Raffaello Mungai

Keyword(s):

Breast Cancer ◽

Case Control Study ◽

Postoperative Radiotherapy ◽

Survival Rates ◽

Radical Mastectomy ◽

Case Control ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Retrospective Case ◽

Control Study

The role of postoperative radiotherapy in N- breast cancer with centrally or medially located tumors is still controversial. The authors report the results of a retrospective non-randomized case-control study of T1–2 N- breast cancer patients with centrally or medially located tumors, treated or not with postoperative radiotherapy after radical mastectomy. Sixty-four patients were treated with postoperative radiotherapy (Co-60) to the internal mammary chain and supraclavicular nodes. Sixty-four control cases, matched by T size and site, N status, age and menstrual status and simply followed-up after radical mastectomy were selected. No significant differences in actuarial recurrence and NED survival rates were observed at 5 years in the 2 compared groups, thus indicating that postoperative radiotherapy for patients with N- centrally or medially located breast cancers is not worthwhile treatment policy.

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Anthracyclines in basal breast cancer: The NCIC-CTG trial MA5 comparing adjuvant CMF to CEF

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.519 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 519-519 ◽

Cited By ~ 1

Author(s):

M. Cheang ◽

S. K. Chia ◽

D. Tu ◽

S. Jiang ◽

L. E. Shepherd ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Hormone Receptors ◽

Premenopausal Women ◽

Population Based ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Basal Breast Cancer ◽

Significant Difference

519 Background: MA5 randomized premenopausal women with node-positive early breast cancers to cyclophosphamide- methotrexate-fluorouracil (CMF) or cyclophosphamide-epirubicin-fluorouracil (CEF) adjuvant chemotherapy. This and other trials have shown that adjuvant regimens containing anthracyclines confer significant survival benefit to breast cancer patients. Meta-analyses have revealed most benefit in women with HER2(+) or TOPO2 (+) tumors. Population-based data suggest that patients with a core basal phenotype (negative for hormone receptors and HER2, positive for CK5/6 or EGFR) conversely have worse survival on anthracycline containing vs. CMF regimens. Here we test the hypothesis specified a priori that for basal breast cancers anthracyclines may be inferior, using data from MA5. Methods: From 710 patients in MA5, blocks suitable for tissue microarray construction were recovered for 549. Immunohistochemistry for ER, PR, HER2, Ki67, CK5/6 and EGFR was obtained, allowing stratification of 511 cases into intrinsic biological subtypes by published methods (Cheang MC et al. Clin Cancer Res 2008;14:1368–76). Prespecified analyses were conducted independently by the NCIC- CTG statistical centre. Results: In the CEF arm, patients with core basal tumors had a hazard ratio of 1.8 (log rank p=0.02) for overall survival (OS) relative to the other biological subtypes. In the CMF arm, there was no significant difference (HR 0.9, p = 0.7). The interaction between core basal status and treatment was borderline significant (p=0.06). Relapse free survival differences did not reach significance. Conclusions: Data from this randomized trial supports the hypothesis that anthracycline containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal breast cancer. [Table: see text] No significant financial relationships to disclose.

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Prognostic Role of Hedgehog-GLI1 Signaling Pathway in Aggressive and Metastatic Breast Cancers

Current Drug Metabolism ◽

10.2174/1389200221666200122120625 ◽

2020 ◽

Vol 21 (1) ◽

pp. 33-43 ◽

Cited By ~ 1

Author(s):

Prasuja Rokkam ◽

Shailender Gugalavath ◽

Deepak Kakara Gift Kumar ◽

Rahul Kumar Vempati ◽

Rama Rao Malla

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Neural Development ◽

Splice Variants ◽

Metastatic Breast ◽

Basic Function ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Aberrant Expression ◽

Cellular Processes

Glioma-associated oncogene homolog 1 (GLI1) is reported as an amplified gene in human glioblastoma cells. It is a krupple like transcription factor, belonging to the zinc finger family. The basic function of GLI1 is normal neural development at various stages of human. The GLI1 gene was first mapped on the chromosome sub-bands 12q13.3-14.1. Further, single nucleotide polymorphism is mostly observed in translating a region of 5’ and 3’- UTR of GLI1 gene in addition to two post-transcriptional splice variants, GLIΔN and tGLI. Additionally, it also regulates a plethora of gene which mediates crucial cellular processes like proliferation, differentiation, oncogenesis, EMT, and metastasis. It also regulates tumor tolerance, chemoresistance, and radioresistance. Aberrant expression of GLI1 predicts the poor survival of breast cancer patients. GLI1 is an essential mediator of the SHH signaling pathway regulating self-renewal of stem cells, angiogenesis, and expression of FOXS1, CYR61. GLI1 mediated HH pathway can induce apoptosis. Hence, GLI1 can be a future diagnostic, prognostic marker, and as well as a potent target of therapeutics in breast cancer.

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Iodine Map Radiomics in Breast Cancer: Prediction of Metastatic Status

Cancers ◽

10.3390/cancers13102431 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2431

Author(s):

Lukas Lenga ◽

Simon Bernatz ◽

Simon S. Martin ◽

Christian Booz ◽

Christine Solbach ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast ◽

Principal Component ◽

Validation Dataset ◽

Dual Energy Ct ◽

Cancer Tissue ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Iodine Map ◽

Iodine Maps

Dual-energy CT (DECT) iodine maps enable quantification of iodine concentrations as a marker for tissue vascularization. We investigated whether iodine map radiomic features derived from staging DECT enable prediction of breast cancer metastatic status, and whether textural differences exist between primary breast cancers and metastases. Seventy-seven treatment-naïve patients with biopsy-proven breast cancers were included retrospectively (41 non-metastatic, 36 metastatic). Radiomic features including first-, second-, and higher-order metrics as well as shape descriptors were extracted from volumes of interest on iodine maps. Following principal component analysis, a multilayer perceptron artificial neural network (MLP-NN) was used for classification (70% of cases for training, 30% validation). Histopathology served as reference standard. MLP-NN predicted metastatic status with AUCs of up to 0.94, and accuracies of up to 92.6 in the training and 82.6 in the validation datasets. The separation of primary tumor and metastatic tissue yielded AUCs of up to 0.87, with accuracies of up to 82.8 in the training, and 85.7 in the validation dataset. DECT iodine map-based radiomic signatures may therefore predict metastatic status in breast cancer patients. In addition, microstructural differences between primary and metastatic breast cancer tissue may be reflected by differences in DECT radiomic features.

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Triple negative aggressive phenotype controlled by miR-135b and miR-365: new theranostics candidates

Scientific Reports ◽

10.1038/s41598-021-85746-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gloria Bertoli ◽

Claudia Cava ◽

Fabio Corsi ◽

Francesca Piccotti ◽

Cristina Martelli ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Triple Negative ◽

Differentially Expressed ◽

Tumor Control ◽

Breast Cancers ◽

Basal Breast Cancer ◽

Therapeutic Molecules ◽

Invasive Capacity ◽

Tnbc Subtype

AbstractTriple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific therapeutic treatments. These aspects cause the high negative prognosis of patients with this type of tumor. The analysis of the molecular profiles of TNBC samples has allowed a better characterization of this tumor, supporting the search for new reliable diagnostic markers. To this end, we have developed a bioinformatic approach to integrate networks of genes differentially expressed in basal breast cancer compared to healthy tissues, with miRNAs able to regulate their expression. We studied the role of these miRNAs in TNBC subtype cell lines. We therefore identified two miRNAs, namely miR-135b and miR-365, with a central role in regulating the altered functional pathways in basal breast cancer. These two miRNAs are differentially expressed in human TNBC immunohistochemistry-selected tissues, and their modulation has been shown to play a role in the proliferation of tumor control and its migratory and invasive capacity in TNBC subtype cell lines. From the perspective of personalized medicine, we managed to modulate the expression of the two miRNAs in organotypic cultures, suggesting their possible use as diagnostic and therapeutic molecules. miR-135b and miR-365 have a key role in TNBC, controlling proliferation and invasion. Their detection could be helpful in TNBC diagnosis, while their modulation could become a new therapeutic tool for TNBC.

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Comparison of survival in non-metastatic inflammatory and other T4 breast cancers: a SEER population-based analysis

BMC Cancer ◽

10.1186/s12885-021-07855-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dechuang Jiao ◽

Jingyang Zhang ◽

Jiujun Zhu ◽

Xuhui Guo ◽

Yue Yang ◽

...

Keyword(s):

Breast Cancer ◽

Cox Model ◽

Survival Rates ◽

Tumor Grade ◽

Population Based ◽

Rank Test ◽

Breast Cancers ◽

Significant Independent Predictor ◽

Cancer Specific Survival ◽

7Th Edition

Abstract Background Previous studies have reported poor survival rates in inflammatory breast cancer (IBC) patients than non-inflammatory local advanced breast cancer (non-IBC) patients. However, until now, the survival rate of IBC and other T4 non-IBC (T4-non-IBC) patients remains unexplored. Methods Surveillance, Epidemiology, and End Results (SEER) database was searched to identify cases with confirmed non-metastatic IBC and T4-non-IBC who had received surgery, chemotherapy, and radiotherapy between 2010 and 2015. IBC was defined as per the American Joint Committee on Cancer (AJCC) 7th edition. Breast Cancer-Specific Survival (BCSS) was estimated by plotting the Kaplan-Meier curve and compared across groups by using the log-rank test. Cox model was constructed to determine the association between IBC and BCSS after adjusting for age, race, stage of disease, tumor grade and surgery type. Results Out of a total of 1986 patients, 37.1% had IBC and mean age was 56.6 ± 12.4. After a median follow-up time of 28 months, 3-year BCSS rate for IBC and T4-non-IBC patients was 81.4 and 81.9%, respectively (log-rank p = 0.398). The 3-year BCSS rate in HR−/HER2+ cohort was higher for IBC patients than T4-non-IBC patients (89.5% vs. 80.8%; log-rank p = 0.028), and in HR−/HER2- cohort it was significantly lower for IBC patients than T4-non-IBC patients (57.4% vs. 67.5%; log-rank p = 0.010). However, it was identical between IBC and T4-non-IBC patients in both HR+/HER2- (85.0% vs. 85.3%; log-rank p = 0.567) and HR+/HER2+ (93.6% vs. 91.0%, log-rank p = 0.510) cohorts. After adjusting for potential confounding variables, we observed that IBC is a significant independent predictor for survival of HR−/HER2+ cohort (hazards ratio [HR] = 0.442; 95% CI: 0.216–0.902; P = 0.025) and HR−/HER2- cohort (HR = 1.738; 95% CI: 1.192–2.534; P = 0.004). Conclusions Patients with IBC and T4-non-IBC had a similar BCSS in the era of modern systemic treatment. In IBC patients, the HR−/HER2+ subtype is associated with a better outcome, and HR−/HER2- subtype is associated with poorer outcomes as compared to the T4-non-IBC patients.

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The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

Nature Communications ◽

10.1038/s41467-020-20173-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Jia-Wern Pan ◽

Muhammad Mamduh Ahmad Zabidi ◽

Pei-Sze Ng ◽

Mei-Yee Meng ◽

Siti Norhidayu Hasan ◽

...

Keyword(s):

Breast Cancer ◽

Somatic Mutations ◽

Checkpoint Inhibitors ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Breast Tumours ◽

Different Populations ◽

Caucasian Women ◽

Molecular Landscape ◽

Immune Score

AbstractMolecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

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Abnormal Long Non-Coding RNAs Expression Patterns Have the Potential Ability for Predicting Survival and Treatment Response in Breast Cancer

Genes ◽

10.3390/genes12070996 ◽

2021 ◽

Vol 12 (7) ◽

pp. 996

Author(s):

Ana Carolina Pavanelli ◽

Flavia Rotea Mangone ◽

Luciana R. C. Barros ◽

Juliana Machado-Rugolo ◽

Vera L. Capelozzi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Predictive Value ◽

Expression Patterns ◽

Survival Rates ◽

In Silico Analysis ◽

Cancer Prognosis ◽

Response To Treatment ◽

Breast Cancer Patients ◽

Non Coding Rnas

Abnormal long non-coding RNAs (lncRNAs) expression has been documented to have oncogene or tumor suppressor functions in the development and progression of cancer, emerging as promising independent biomarkers for molecular cancer stratification and patients’ prognosis. Examining the relationship between lncRNAs and the survival rates in malignancies creates new scenarios for precision medicine and targeted therapy. Breast cancer (BRCA) is a heterogeneous malignancy. Despite advances in its molecular classification, there are still gaps to explain in its multifaceted presentations and a substantial lack of biomarkers that can better predict patients’ prognosis in response to different therapeutic strategies. Here, we performed a re-analysis of gene expression data generated using cDNA microarrays in a previous study of our group, aiming to identify differentially expressed lncRNAs (DELncRNAs) with a potential predictive value for response to treatment with taxanes in breast cancer patients. Results revealed 157 DELncRNAs (90 up- and 67 down-regulated). We validated these new biomarkers as having prognostic and predictive value for breast cancer using in silico analysis in public databases. Data from TCGA showed that compared to normal tissue, MIAT was up-regulated, while KCNQ1OT1, LOC100270804, and FLJ10038 were down-regulated in breast tumor tissues. KCNQ1OT1, LOC100270804, and FLJ10038 median levels were found to be significantly higher in the luminal subtype. The ROC plotter platform results showed that reduced expression of these three DElncRNAs was associated with breast cancer patients who did not respond to taxane treatment. Kaplan–Meier survival analysis revealed that a lower expression of the selected lncRNAs was significantly associated with worse relapse-free survival (RFS) in breast cancer patients. Further validation of the expression of these DELncRNAs might be helpful to better tailor breast cancer prognosis and treatment.

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