scholarly journals Hormonal regulation of Semaphorin 7a in ER+ breast cancer drives therapeutic resistance

2019 ◽  
Author(s):  
Lyndsey S Crump ◽  
Garhett Wyatt ◽  
Taylor R Rutherford ◽  
Jennifer K Richer ◽  
Weston W Porter ◽  
...  
Keyword(s):  
Endocrine Therapy ◽  
Hormonal Regulation ◽  
Lung Metastases ◽  
Survival Rates ◽  
Poor Response ◽  
Breast Cancers ◽  
Tumor Resistance ◽  
Survival Signaling

ABSTRACTApproximately 70% of all breast cancers are estrogen receptor positive (ER+BC) and endocrine therapy has improved survival for patients with ER+BC. Yet, up to half of these tumors recur within 20 years. Recurrent ER+BCs develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER+BC. We found that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER+BC. We show that SEMA7A is hormonally regulated in ER+BC, but its expression does not uniformly decrease with anti-estrogen treatments. Additionally, overexpression of SEMA7A in ER+ cell lines drives increased in vitro growth in the presence of estrogen-deprivation, tamoxifen, and fulvestrant. In in vivo studies, we found that SEMA7A confers primary tumor resistance to fulvestrant and, importantly, induced lung metastases. Finally, we identify pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors and propose that targeting with inhibitors of survival signaling such as venetoclax may have efficacy for treating SEMA7A+ tumors.SIGNIFICANCEWe report that SEMA7A predicts for, and likely contributes to, poor response to standard-of-care therapies and suggest that patients with SEMA7A+ER+ tumors may benefit from alternative therapeutic strategies.

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

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.

scholarly journals Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2268
Author(s):  
Mélanie Lavaud ◽  
Mathilde Mullard ◽  
Robel Tesfaye ◽  
Jérôme Amiaud ◽  
Mélanie Legrand ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Lung Metastases ◽  
Poor Response ◽  
Response To Treatment ◽  
Osteosarcoma Cell ◽  
Sequencing Analysis ◽  
Protein Ubiquitination

Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan–Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS.

scholarly journals Neoadjuvant Endocrine Therapy in Breast Cancer Management: State of the Art

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 902
Author(s):  
Florence Lerebours ◽  
Luc Cabel ◽  
Jean-Yves Pierga
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Survival Rates ◽  
Breast Conserving Surgery ◽  
Breast Cancers ◽  
Neoadjuvant Endocrine Therapy ◽  
Cancer Management ◽  
Surgery Outcome ◽  
Her2 Breast Cancer

Endocrine therapy is the mainstay of treatment in HR+/HER2- breast cancers, which represent about 70% of all breast cancers. Neoadjuvant therapy has been developed since the 1990s to address several issues, including breast-conserving surgery (BCS) and improvement of survival rates. For a long time, neoadjuvant endocrine therapy (NET) was confined to frail patients in order to improve surgery outcome. Since the 2000s, NET now plays a central role as a research tool for predictive endocrine sensitivity biomarkers and targeted therapies. One of the major issues in early HR+/HER2- breast cancer is to identify patients in whom chemotherapy can be safely withheld. In vivo assessment of response to NET might be the best treatment strategy to address this issue.

scholarly journals GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers

2020 ◽  
Author(s):  
Gaia Bianco ◽  
Mairene Coto-Llerena ◽  
John Gallon ◽  
Stephanie Taha-Mehlitz ◽  
Venkatesh Kancherla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Synthetic Lethality ◽  
Poor Response ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Synthetic Lethal ◽  
Er Positive

SummarySynthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 induce apoptosis in GATA3-deficient models in vitro, in vivo and in patient-derived organoids (PDOs) harboring GATA3 somatic mutation. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a novel therapeutic target in the substantial cohort of ER-positive, GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.

scholarly journals Hormonal Regulation of Semaphorin 7a Promotes Therapeutic Resistance in Breast Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1021-A1022
Author(s):  
Lyndsey Crump ◽  
Jennifer K Richer ◽  
Weston Porter ◽  
Traci Lyons
Keyword(s):  
Drug Resistance ◽  
Cell Survival ◽  
Endocrine Therapy ◽  
Multi Drug Resistance ◽  
Estrogen Deprivation ◽  
Er Targeting ◽  
Survival Signaling

Abstract Background: The majority of all breast cancers (BC) are estrogen receptor positive (ER+). While ER-targeting endocrine therapies have improved patient survival, many of these tumors develop drug resistance and recur within 20 years. Therefore, novel targets are needed to predict for recurrence and to treat recurrent ER+BC. Previous reports describe a tumor-promotional role for Semaphorin 7A (SEMA7A) in ER- disease; yet, the role of SEMA7A in ER+ disease is poorly characterized. Hypothesis: SEMA7A promotes cell survival and drug resistance in ER+ BC. Methods: We overexpressed SEMA7A in ER+ BC cells, then used the ER-targeting agents tamoxifen and fulvestrant to test how SEMA7A-expressing cells respond to endocrine therapy. In vitro, we used proliferation and cell survival assays. In vivo, we implanted ER+ BC cells, then treated the animals with fulvestrant to measure how SEMA7A affects tumor growth and metastasis. We also utilized drug resistant cells, which have high endogenous SEMA7A levels, to measure markers of stemness and multi-drug resistance via flow cytometry. Results: We first found that SEMA7A expression correlates with decreased relapse free survival in patients with ER+BC who received endocrine therapy (Kmplotter; p=0.042). We also observe that SEMA7A is hormonally regulated in ER+BC, but its expression does not uniformly decrease with endocrine therapy agents. Instead, long term estrogen deprivation and ER-targeting drug treatments increase SEMA7A expression, likely through the action of other hormone receptors such as the androgen receptor, which also increases with long term estrogen deprivation. Further, in ER+ cell lines, overexpression of SEMA7A promotes in vitro growth in the face of estrogen-deprivation, tamoxifen, or fulvestrant treatments. In vivo, SEMA7A promotes fulvestrant resistance in the primary tumor and induces lung metastases. Finally, we report that pro-survival signaling is a therapeutic vulnerability of ER+SEMA7A+ tumors. Conclusion: These studies describe that SEMA7A promotes drug resistance in ER+ BC. We propose that targeting pro-survival signaling may prove efficacious for treating SEMA7A+ tumors, which are less likely to respond to endocrine therapies.

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
JiangSheng Zhao ◽  
GuoFeng Chen ◽  
Jingqi Li ◽  
Shiqi Liu ◽  
Quan Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
Lung Metastases ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
And Migration ◽  
Healthy Liver

Abstract Background PR55α plays important roles in oncogenesis and progression of numerous malignancies. However, its role in hepatocellular carcinoma (HCC) is unclear. This study aims to characterize the functions of PR55α in HCC. Methods PR55α expressions in HCC tissues and paired healthy liver samples were evaluated using Western blot and tissue microarray immunohistochemistry. We knocked down the expression of PR55α in SMMC-7721 and LM3 cell lines via small interfering and lentivirus. In vitro cell counting, colony formation, migration and invasion assays were performed along with in vivo xenograft implantation and lung metastases experiments. The potential mechanisms involving target signal pathways were investigated by RNA-sequencing. Results PR55α expression level was suppressed in HCC tissues in comparison to healthy liver samples. Decreased PR55α levels were correlated with poorer prognosis (P = 0.0059). Knockdown of PR55α significantly promoted cell proliferation and migration, induced repression of the cell cycle progression and apoptosis in vitro while accelerating in vivo HCC growth and metastasis. Mechanistic analysis indicated that PR55α silencing was involved with MAPK/AKT signal pathway activation and resulted in increased phosphorylation of both AKT and ERK1/2. Conclusions This study identifies PR55α to be a candidate novel therapeutic target in the treatment of HCC.

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 Bone marrow mesenchymal stem cells promote prostate cancer cell stemness via cell–cell contact to activate the Jagged1/Notch1 pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-wen Cheng ◽  
Li-xia Duan ◽  
Yang Yu ◽  
Pu Wang ◽  
Jia-le Feng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Cell Contact ◽  
Activity Levels ◽  
Tumor Resistance ◽  
Cell Cell

Abstract Background Mesenchymal stem cells (MSCs) play a crucial role in cancer development and tumor resistance to therapy in prostate cancer, but the influence of MSCs on the stemness potential of PCa cells by cell–cell contact remains unclear. In this study, we investigated the effect of direct contact of PCa cells with MSCs on the stemness of PCa and its mechanisms. Methods First, the flow cytometry, colony formation, and sphere formation were performed to determine the stemness of PCaMSCs, and the expression of stemness-related molecules (Sox2, Oct4, and Nanog) was investigated by western blot analysis. Then, we used western blot and qPCR to determine the activity levels of two candidate pathways and their downstream stemness-associated pathway. Finally, we verified the role of the significantly changed pathway by assessing the key factors in this pathway via in vitro and in vivo experiments. Results We established that MSCs promoted the stemness of PCa cells by cell–cell contact. We here established that the enhanced stemness of PCaMSCs was independent of the CCL5/CCR5 pathway. We also found that PCaMSCs up-regulated the expression of Notch signaling-related genes, and inhibition of Jagged1-Notch1 signaling in PCaMSCs cells significantly inhibited MSCs-induced stemness and tumorigenesis in vitro and in vivo. Conclusions Our results reveal a novel interaction between MSCs and PCa cells in promoting tumorigenesis through activation of the Jagged1/Notch1 pathway, providing a new therapeutic target for the treatment of PCa.

scholarly journals Effects of Vitrification on the Blastocyst Gene Expression Profile in a Porcine Model

2021 ◽  
Vol 22 (3) ◽  
pp. 1222
Author(s):  
Cristina Cuello ◽  
Cristina A. Martinez ◽  
Josep M. Cambra ◽  
Inmaculada Parrilla ◽  
Heriberto Rodriguez-Martinez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Analysis ◽  
Survival Rates ◽  
Control Group ◽  
P Value ◽  
Transcriptome Profile ◽  
Embryo Viability ◽  
The Impact

This study was designed to investigate the impact of vitrification on the transcriptome profile of blastocysts using a porcine (Sus scrofa) model and a microarray approach. Blastocysts were collected from weaned sows (n = 13). A total of 60 blastocysts were vitrified (treatment group). After warming, vitrified embryos were cultured in vitro for 24 h. Non-vitrified blastocysts (n = 40) were used as controls. After the in vitro culture period, the embryo viability was morphologically assessed. A total of 30 viable embryos per group (three pools of 10 from 4 different donors each) were subjected to gene expression analysis. A fold change cut-off of ±1.5 and a restrictive threshold at p-value < 0.05 were used to distinguish differentially expressed genes (DEGs). The survival rates of vitrified/warmed blastocysts were similar to those of the control (nearly 100%, n.s.). A total of 205 (112 upregulated and 93 downregulated) were identified in the vitrified blastocysts compared to the control group. The vitrification/warming impact was moderate, and it was mainly related to the pathways of cell cycle, cellular senescence, gap junction, and signaling for TFGβ, p53, Fox, and MAPK. In conclusion, vitrification modified the transcriptome of in vivo-derived porcine blastocysts, resulting in minor gene expression changes.

Sign in / Sign up

Export Citation Format

Share Document