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 miR-200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer

2017 ◽  
Author(s):  
Cailu Song ◽  
Jin Wang ◽  
Hua Wang ◽  
Peng Liu ◽  
Longzhong Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Target Genes ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Mcf 7

AbstractResistance to trastuzumab remains a major obstacle in HER2-overexpressing breast cancer treatment. miR-200c is important for many functions in cancer stem cells (CSCs), including tumor recurrence, metastasis and resistance. We hypothesized that miR-200c contributes to trastuzumab resistance and stemness maintenance in HER2-overexpressing breast cancer. In this study, we used HER2-positive SKBR3, HER2-negative MCF-7, and their CD44+CD24- phenotype mammospheres SKBR3-S and MCF-7-S to verify. Our results demonstrated that miR-200c was weakly expressed in breast cancer cell lines and cell line stem cells. Overexpression of miR-200c resulted in a significant reduction in the number of tumor spheres formed and the population of CD44+CD24- phenotype mammospheres in SKBR3-S. Combining miR-200c with trastuzumab can significantly reduce proliferation and increase apoptosis of SKBR3 and SKBR3-S. Overexpression of miR-200c also eliminated its downstream target genes. These genes were highly expressed and positively related in breast cancer patients. Overexpression of miR-200c also improved the malignant progression of SKBR3-S and SKBR3 in vivo. miR-200c plays an important role in the maintenance of the CSC-like phenotype and increases drug sensitivity to trastuzumab in HER2+ cells and stem cells.Summary statementmiRNAs are critical in stemness maintenance and drug resistance. These data link maintenance of the stemness-related phenotype and the sensitivity of HER2+ breast cancer to miR-200c in response to trastuzumab.

scholarly journals O80: GREMLIN-1 PROMOTES TUMOURIGENESIS AND METASTASIS IN HER2 POSITIVE BREAST CANCER

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
C Zabkiewicz ◽  
L Ye ◽  
R Hargest
Keyword(s):  
Breast Cancer ◽  
Cellular Growth ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Mesenchymal Transition ◽  
Her2 Breast Cancer ◽  
Bmp Signalling ◽  
Gremlin 1

Abstract Introduction HER2 over-expression denotes poor prognosis in breast cancers.Bone morphogenetic protein(BMP) signalling is known to interact with EGF signalling, co-regulating breast cancer progression.BMP antagonist Gremlin-1 may influence breast cancer disease progression, but this remains unexplored in HER2 positive breast cancers. Method GREM1 and HER2 expression, and clinical outcomes were examined in clinical cohorts.GREM1 overexpression or pEF control plasmid were transduced into BT474 HER2+breast cancer cells. In vitro function tests using BT474 pEF and BT474GREM1cells include 2D/3D growth, migration, and expression of epithelial to mesenchymal transition(EMT)markers. Signalling cascades were examined in BT474 treated with RhGremlin-1. In vivo, BALB/c nude mice underwent either mammary injection or intra-cardiac injection of BT474pEF or BT474GREM1 cells and disease burden assessed. Result GREM1 expression correlates with HER2 in breast tumours(p=0.03) and is higher in metastatic HER2 positive cancers (p = 0.04). HER2 positive patients with high GREM1 have poor survival(p = 0.0002). BT474GREM1cells have up-regulated markers of EMT compared to control. BT474 RhGremlin-1 treated cells have active AKT pathway signalling, independent of BMP signalling. In vitro,  BT474GREM1cells significantly proliferate and migrate compared to control(p<0.05 and p < 0.001).This is confirmed in vivo,  BT474GREM1 mice grew significantly larger mammary tumours(p<0.05) and had more PETCT metastatic hotspots. Conclusion Gremlin-1 is correlated with poor outcomes in HER2 patients and promotes breast cancer cellular growth, migration and metastasis.Gremlin-1 is a novel area of research with potential as a prognostic biomarker and therapeutic target for personalised, effective, breast cancer outcomes. Take-home message BMP antagonists are gaining interest for their potential in breast cancer prognosis and therapeutics.This novel area of research shows BMP antagonist Gremlin-1 is of importance in HER2 positive breast cancers. DRAGONS DEN

scholarly journals miR-342-5p as a Potential Regulator of HER2 Breast Cancer Cell Growth

MicroRNA ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 155-165 ◽  
Author(s):  
Evita Maria Lindholm ◽  
Suvi-Katri Leivonen ◽  
Eldri Undlien ◽  
Daniel Nebdal ◽  
Anna Git ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Breast Cancer Cell Lines ◽  
Nucleotide Exchange ◽  
Her2 Positive ◽  
Her2 Breast Cancer

Background: HER2 positive Breast Cancers (BC) have aggressive behavior and poor prognosis. Previously, we have identified miR-342-5p as an upstream regulator of HER2 signaling, as well as inhibitor of HER2 positive BC cell line growth. Objective: Here, we aimed to further investigate the molecular mechanisms behind miR-342-5pinduced HER2 pathway deregulation. </P><P> Method: Two HER2 amplified breast cancer cell lines were transiently transfected with miR-342-5p mimic or negative control, and gene expression was analyzed by Agilent microarrays. Three clinical datasets with BC patients were used to identify correlations between candidate genes and miR-342- 5p, and associations with survival. Results: Pathway analyses of all deregulated genes revealed a significant suppression of the HER2 downstream pathways ERK/MAPK and SAPK/JNK, whereas the miR-342-5p predicted target genes were enriched for pathways associated with cell motility.Biological functions linked to mitochondrial stability were ranked among the top toxicological functions in both gene lists. Among the most deregulated genes, Cytochrome B5 Reductase 3 (CYB5R3) and Rap Guanine Nucleotide Exchange Factor 6 (RAPGEF6) significantly anticorrelated and correlated, respectively, with miR-342-5p in all three clinical BC datasets. Low CYB5R3 levels and high RAPGEF6 levels were significantly associated with survival, although this was not directly associated with HER2 expression. Conclusion: Our data suggest that miR-342-5p overexpression in HER2 positive BC cell lines elicits broad effects on HER2 downstream signaling, cell motility and mitochondrial stability. Together these effects may render cells less proliferative and more sensitive to cellular stress.

scholarly journals NCAPG confers trastuzumab resistance via activating SRC/STAT3 signaling pathway in HER2-positive breast cancer

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Lili Jiang ◽  
Liangliang Ren ◽  
Han Chen ◽  
Jinyuan Pan ◽  
Zhuojun Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Recurrence ◽  
Early Recurrence ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Structural Maintenance Of Chromosome ◽  
Underlying Mechanisms

AbstractHER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.

Pre-clinical analysis of the CDK4/6 inhibitor palbociclib in HER2-positive breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12520-e12520 ◽  
Author(s):  
Bilal ElChaarani ◽  
Hillary Stires ◽  
Paula Raffin Pohlmann ◽  
Rebecca Riggins
Keyword(s):  
Breast Cancer ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Dependent Manner ◽  
Her2 Positive ◽  
Western Blots ◽  
Her2 Breast Cancer ◽  
Presence And Absence ◽  
Dose Dependent

e12520 Background: There has been substantial progress in treatment of metastatic HER2+ breast cancer, unfortunately, treatment progression of the disease is universal. Palbociclib is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that is FDA approved in combination with endocrine therapy for treatment of patients with ER+ metastatic breast cancer. Here we present pre-clinical studies in HER2+ breast cancer cell lines investigating whether addition of palbociclib to the combination of trastuzumab and pertuzumab (TP) is an effective therapy, and whether we could identify predictive biomarkers for palbociclib in this setting. Methods: Crystal violet assays to measure growth of BT-474 (HER2+, ER+), SKBr3 (HER2+, ER-) and MDA-MB-361 (HER2+, ER+ but resistant to TP) were performed in the presence and absence of TP (5 µg/ml each) with increasing concentrations of palbociclib (25-500 µg/ml). Western blots were performed in the presence and absence of TP with and without palbociclib to demonstrate efficacy of TP (blocking phosphorylation of HER2), palbociclib (blocking phosphorylation of Rb), and expression of NIMA-related kinase 2 (NEK2), an established downstream target of CDK4 in HER2+ breast cancer cells. Results: We found growth inhibition in response to palbociclib as single agent in a dose-dependent manner in BT-474, SKBr3, and MDA-MB-361 cells (P < 0.05). Treatment with TP prevented growth in BT-474 and SKBr3 cells to such a great extent that an additive effect between TP and palbociclib was not detectable. However, treatment with palbociclib maintained a dose-dependent decrease in growth in the presence of TP in MDA-MB-361 cells (P < 0.05). Western blots showed decreased expression of pHER2 in response to TP in BT-474 and SKBr3, but not in MDA-MB-361. Treatment with palbociclib decreased pRB in BT474, SKBr3, and MDA-MB-361 with or without TP. NEK2 expression, however, was not affected in any of these cell lines. Conclusions: Palbociclib has an inhibitory effect in resistant and non-resistant HER2-positive cell lines suggesting palbociclib represents an alternate targeting pathway for growth inhibition. Our initial work did not show reliable biomarkers to predict palbociclib effects.

scholarly journals Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis

2017 ◽  
Vol 9 (4) ◽  
pp. 235-252 ◽  
Author(s):  
Rabah Rashad Falah ◽  
Wamidh H. Talib ◽  
Seba Jamal Shbailat
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Therapeutic Option ◽  
Serum Levels ◽  
In Vivo Studies ◽  
Breast Cancer Cell Lines ◽  
Th2 Immune Response ◽  
Immune System Modulation ◽  
P Cells

Background: The effects of metformin (MET) and curcumin (CUR) single treatments have been tested against breast cancer; however, their combination has not been explored. Here, we evaluated the antitumor activity of MET and CUR combination against breast cancer in mice. Materials and methods: The antiproliferative activity of single and combined treatments against breast cancer cell lines was determined. Vascular endothelial growth factor (VEGF) and Trp53 expression was examined in EMT6/P cells. In vivo studies were carried out by inoculating BALB/c mice with EMT6/P cells and examining tumor growth and apoptosis induction in tumor sections. Furthermore, serum levels of different cytokines and transaminases and creatinine were measured to detect the immune response and toxicity, respectively. Results: The combination treatment exhibited the highest effects against tumor proliferation and growth. It significantly reduced VEGF expression, induced Trp53 independent apoptosis, triggered Th2 immune response and showed no toxicity. Conclusion: The combination can be a potential therapeutic option to treat breast cancer. However, further testing is needed to measure the exact serum levels of MET and CUR and to further explain the obtained results.

scholarly journals SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Akitoshi Nakayama ◽  
Masataka Yokoyama ◽  
Hidekazu Nagano ◽  
Ikki Sakuma ◽  
Naoko Hashimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cholesterol Synthesis ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Breast Cancer Cell Lines ◽  
Mutant P53 ◽  
Dependent Manner ◽  
Gain Of Function ◽  
Necessary And Sufficient

Abstract p53 is mutated more than half of human cancers, and mutant p53, a gain of function, can actively have functional consequences with tumorigenesis. However, its action of molecular mechanisms, particularly in vivo conditions, has not been fully are clarified. Here, we generated KO and KI (R280K) breast cancer cell lines for p53 using CRISPR/Cas9 system, and then performed a three-dimensional culture model. We found that the introduction of mutant p53 was solely able to mediate the transformation to poor architectural structure. Interestingly, our findings in statin-effect along with cholesterol synthesis pathway, especially isoprenoid dependency, revealed that this pathway is necessary and sufficient for the regulation of malignant architecture in SREBP2-dependent manner with cooperatively being controlled by mutant p53 on 3D-cultured breast cancer. Furthermore, in accordance with the malignancy progresses, SREBP2 was accumulated in nuclear and nuclear membrane portion with enhancement in malignant formation. In addition, we found that mutant p53 interacts with SREBP2, and consistently mutant p53 was associated with DHCR7 promoter in parallel with binding pattern of SREBP2. Thus, our results provide the novel insight into the mutant p53, a gain of function, and its linkage to poor architectural structure in 3D-cultured breast cancer cells via SREBP2-dependent isoprenoids regulation as potential therapeutic targets.

scholarly journals Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade. The SePHER Study.

2020 ◽  
Author(s):  
Giulia Bon ◽  
Laura Pizzuti ◽  
Valentina Laquintana ◽  
Rossella Loria ◽  
Manuela Porru ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Second Line ◽  
First Line ◽  
Her2 Positive ◽  
Her2 Breast Cancer

Abstract Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.Methods: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2+breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2+ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.Results: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p=0.0006 and 0.03 for OS and PFS2, respectively). Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

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.

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