scholarly journals The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Florian Wegwitz ◽  
Evangelos Prokakis ◽  
Anastasija Pejkovska ◽  
Robyn Laura Kosinsky ◽  
Markus Glatzel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Ubiquitin Ligase ◽  
Transcriptional Activation ◽  
Breast Cancer Subtype ◽  
Mammary Tumorigenesis ◽  
Human Tumor ◽  
Her2 Positive ◽  
Number Of Patients

Abstract The HER2-positive breast cancer subtype (HER2+-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2+-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment strategies. Epigenetic regulators are commonly misregulated in cancer and represent attractive molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by the heterodimeric ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2+-BC. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin-cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2+-BC, revealing the H2B monoubiquitination axis as a possible tumor context-dependent therapeutic target in breast cancer.

scholarly journals RNF40-dependent epigenetic regulation of actin cytoskeletal dynamics is required for HER2-driven mammary tumorigenesis

2020 ◽  
Author(s):  
Florian Wegwitz ◽  
Evangelos Prokakis ◽  
Anastasija Pejkovska ◽  
Robyn Laura Kosinsky ◽  
Markus Glatzel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Breast Cancer Subtype ◽  
Human Tumor ◽  
Actin Dynamics ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

AbstractThe HER2-driven breast cancer subtype displays a particularly aggressive behavior. Alterations of the epigenome are common in cancers and represent attractive novel molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by its obligate heterodimeric E3 ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2-positive breast cancer. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2-positive breast cancer, revealing the RNF20/RNF40/H2Bub1 axis as a possible tumor context-dependent therapeutic target in breast cancer.Statement of significanceHER2-positive breast cancer patients frequently develop resistance to anti-HER2 therapies. Here we demonstrate that RNF20/RNF40-mediated H2B monoubiquitination supports the oncogenic properties of cancer cells of this subtype by regulating actin dynamics. The RNF20/RNF40/H2Bub1 axis may therefore represent an attractive drug target for novel therapies.

scholarly journals MZ1 co-operates with trastuzumab in HER2 positive breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
María del Mar Noblejas-López ◽  
Cristina Nieto-Jiménez ◽  
Eva M. Galán-Moya ◽  
David Tebar-García ◽  
Juan Carlos Montero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Three Dimensional ◽  
In Vivo Studies ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Number Of Patients ◽  
Bet Inhibitors

Abstract Background Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context, novel drug combinations are needed to increase its antitumor activity. In this work, we have evaluated the efficacy of proteolysis targeting chimera (PROTAC) compounds based on BET inhibitors (BETi) to augment the activity of trastuzumab in HER2+ breast cancer models. Methods BT474 and SKBR3 HER2+ breast cancer cell lines were used. The effects of trastuzumab and the BET-PROTAC MZ1 either alone or in combination, were evaluated using MTT proliferation assays, three-dimensional invasion and adhesion cultures, flow cytometry, qPCR and Western blot. In vivo studies were carried out in a xenografted model in mice. Finally, a Clariom_S_Human transcriptomic array was applied to identify deregulated genes after treatments. Results MZ1 induced a higher antiproliferative effect compared to the BETi JQ1. The combination of MZ1 and -trastuzumab significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone. Evaluation of apoptosis resulted in an increase of cell death following treatment with the combination, and biochemical studies displayed modifications of apoptosis and DNA damage components. In vivo administration of agents alone or combined, to tumors orthotopically xenografted in mice, resulted in a decrease of the tumor volume only after MZ1-Trastuzumab combination treatment. Results from a transcriptomic array indicated a series of newly described transcription factors including HOXB7, MEIS2, TCERG1, and DNAJC2, that were associated to poor outcome in HER2+ breast cancer subtype and downregulated by the MZ1-trastuzumab combination. Conclusions We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development.

scholarly journals p63 at the Crossroads between Stemness and Metastasis in Breast Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2683 ◽  
Author(s):  
Veronica Gatti ◽  
Lucilla Bongiorno-Borbone ◽  
Claudia Fierro ◽  
Margherita Annicchiarico-Petruzzelli ◽  
Gerry Melino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Breast Cancer Subtype ◽  
Physiological Role ◽  
The Past ◽  
Cancer Breast ◽  
Incidence And Mortality ◽  
Cancer Subtype ◽  
Screening Approaches

After lung cancer, breast cancer (BC) is the most frequent cause of cancer death among women, worldwide. Although advances in screening approaches and targeted therapeutic agents have decreased BC incidence and mortality, over the past five years, triple-negative breast cancer (TNBC) remains the breast cancer subtype that displays the worst prognosis, mainly due to the lack of clinically actionable targets. Genetic and molecular profiling has unveiled the high intrinsic heterogeneity of TNBC, with the basal-like molecular subtypes representing the most diffuse TNBC subtypes, characterized by the expression of basal epithelial markers, such as the transcription factor p63. In this review, we will provide a broad picture on the physiological role of p63, in maintaining the basal epithelial identity, as well as its involvement in breast cancer progression, emphasizing its relevance in tumor cell invasion and stemness.

scholarly journals Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 180
Author(s):  
Christina Mertens ◽  
Matthias Schnetz ◽  
Claudia Rehwald ◽  
Stephan Grein ◽  
Eiman Elwakeel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Lung Metastases ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Lipocalin 2 ◽  
Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

scholarly journals Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jun-Xian Du ◽  
Yi-Hong Luo ◽  
Si-Jia Zhang ◽  
Biao Wang ◽  
Cong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
High Risk Group ◽  
Clinical Samples ◽  
Binding Motif ◽  
Ki 67 ◽  
Tissue Samples

Abstract Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

scholarly journals Antioxidants for the Treatment of Breast Cancer: Are We There Yet?

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 205
Author(s):  
Carmen Griñan-Lison ◽  
Jose L. Blaya-Cánovas ◽  
Araceli López-Tejada ◽  
Marta Ávalos-Moreno ◽  
Alba Navarro-Ocón ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Cancer Progression ◽  
Redox Homeostasis ◽  
Breast Carcinogenesis ◽  
Breast Cancer Patients ◽  
Chemopreventive Agents ◽  
Low Degree ◽  
Potential Use

Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on “redoxidomics” or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients.

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