scholarly journals Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis

2018 ◽  
Author(s):  
Soo-Hyun Kim ◽  
Richard P. Redvers ◽  
Lap Hing Chi ◽  
Xiawei Ling ◽  
Andrew J. Lucke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Brain Metastasis ◽  
Histone Deacetylase ◽  
Clinical Relevance ◽  
Histone Deacetylase Inhibitors ◽  
Novel Therapies ◽  
Breast Cancer Brain Metastasis ◽  
The Brain

ABSTRACTBreast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis.SUMMARY STATEMENTWe introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain metastasis and test novel therapies.

TAMI-04. OLFACTORY RECEPTOR 5B21 DRIVES BREAST CANCER BRAIN METASTASIS THROUGH STAT3/NFΚB/CEBPΒ PATHWAY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi198-vi199
Author(s):  
Mao Li ◽  
Markus Schweiger ◽  
Daniel Ryan ◽  
Ichiro Nakano ◽  
Litia Carvalho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Mesenchymal Transition ◽  
Breast Cancer Brain Metastasis ◽  
Metastatic Sites ◽  
The Brain

Abstract Olfactory receptors (ORs), responsible for the sense of smell, play an essential role in various physiological processes outside the nasal epithelium, including cancer. In breast cancer, however, the expression and function of ORs remain understudied. We established a breast cancer metastasis model by intracardiac injection of MDA-MB-231 (231P) in immunocompromised mice and produced a series of derivative cell lines from developed metastatic sites, including the brain-seeking clone (231Br). We examined the significance of ORs transcript abundance in primary and metastatic breast cancer to different tissues, including the brain, bone, and lung. While 20 OR transcripts were differentially expressed in distant metastases, OR5B21 displayed high expression in all three metastatic sites with respect to the primary tumor, especially in brain metastasis with 13 fold higher than the primary site. Metastatic clones showed distinguishing higher invasion biological characteristics compared to parental cells in vivo and in vitro. Knockdown of OR5B21 significantly decreased the invasion and migration of MDA-MB-231 Brain-seeking metastatic cell as well as metastasis to different organs, including the brain, while overexpression of OR5B21 had the opposite effect. Mechanistically, OR5B21 expression was associated with epithelial to mesenchymal transition through the STAT3/NFkB/CEBPβ signaling pathway. We propose OR5B21 (and potentially other ORs) as a novel oncogene contributing to breast cancer brain metastasis and a potential target for adjuvant therapy.

scholarly journals MiR-211 determines brain metastasis specificity through SOX11/NGN2 axis in triple-negative breast cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jhih-Kai Pan ◽  
Cheng-Han Lin ◽  
Yao-Lung Kuo ◽  
Luo-Ping Ger ◽  
Hui-Chuan Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Survival Outcomes ◽  
Poor Survival ◽  
Breast Cancer Brain Metastasis ◽  
High Level

AbstractBrian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood–brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

scholarly journals CircBCBM1 Promotes Breast Cancer Brain Metastasis via miR-125a/BRD4 Axis

2020 ◽  
Author(s):  
Bo Fu ◽  
Wei Liu ◽  
Peng Li ◽  
Li Pan ◽  
Ke Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Breast Cancer Patients ◽  
Breast Cancer Brain Metastasis ◽  
Tumorigenesis And Progression ◽  
And Migration

Abstract Background: Accumulating evidence indicates that circular RNAs (circRNAs) play critical roles in tumorigenesis and progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown.Methods: In this reserch, we validated the expression and characterization of circBCBM1 through RT-qPCR, Sanger sequencing, RNase R assay and fluorescence in situ hybridization (FISH). Functional experiments were performed to determine the effect of circBCBM1 on growth and metastasis of 231-BR cells both in vitro and in vivo. The regulatory mechanisms among circBCBM1, miR-125a (has-miR-125a-5p), and BRD4 (bromodomain containing 4) were investigated by RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter assay and western blot. Results: Our findings demonstrated that circBCBM1 is a stable and cytoplasmic circRNA. Functionally, silencing of circBCBM1 led to decreased proliferation and migration of 231-BR cells whereas elevated circBCBM1 expression showed reverse effects in vitro. These findings were confirmed in vivo in mouse models, as knockdown of circBCBM1 significantly decreased growth and brain metastases of 231-BR cells. Mechanistically, circBCBM1 functions as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 expression and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, the overexpression of circBCBM1 in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients.Conclusions: These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis, which sheds light on the pathogenic mechanism of circBCBM1 and provides translational evidence that circBCBM1 may serve as a novel diagnostic or prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.

scholarly journals BSCI-25. THE ROLE OF THE IFNγ PATHWAY IN BREAST CANCER BRAIN METASTASIS FORMATION

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i5-i5
Author(s):  
Route Pedrosa ◽  
Benjamin Schrijver ◽  
Rute B Marques ◽  
Pieter J M Leenen ◽  
Wim A Dik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
T Cell Response ◽  
Activated T Cells ◽  
Breast Cancer Brain Metastasis

Abstract In previous work, we showed the prominence of the T cell response in the formation of brain metastases of primary ER-negative breast cancers. We also showed that prior co-cultured breast cancer cells with stimulated T lymphocytes bear an overexpression of Guanylate-binding protein 1 (GBP1) and possess an increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to the brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. In the present work, we show that activated CD8+ cytotoxic T lymphocytes, rather than CD4+ lymphocytes, are the main cause of increasing the ability of breast cancer cells to cross the BBB. While synthetic IFNγ does not change the ability of breast cancer cells to cross the BBB, this study shows that the T lymphocyte-secreted IFNγ activates the STAT1-dependent IFNγ pathway in breast cancer cells, enabling them to cross the in vitro BBB. Direct inhibition of soluble IFNγ or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. The results illustrate that IFNγ signaling pathway is one of the crucial pathways in the formation of brain metastasis of ER- breast cancer. The interference with the IFNγ pathway will develop preventive strategies against the formation of brain metastases of breast cancer.

scholarly journals ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Sara Charmsaz ◽  
Ben Doherty ◽  
Sinéad Cocchiglia ◽  
Damir Varešlija ◽  
Attilio Marino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
In Silico ◽  
Ex Vivo ◽  
Metastatic Breast ◽  
Peptide Mimetic ◽  
Breast Cancer Brain Metastasis

Abstract Background Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. Methods Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target’s natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. Results Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. Conclusion ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

scholarly journals Glucose Transporter 3 Is Essential for the Survival of Breast Cancer Cells in the Brain

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1568 ◽  
Author(s):  
Min-Hsun Kuo ◽  
Wen-Wei Chang ◽  
Bi-Wen Yeh ◽  
Yeh-Shiu Chu ◽  
Yueh-Chun Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Glucose Transporter ◽  
Metastatic Breast ◽  
Breast Cancer Brain Metastasis ◽  
The Brain

Breast cancer brain metastasis commonly occurs in one-fourth of breast cancer patients and is associated with poor prognosis. Abnormal glucose metabolism is found to promote cancer metastasis. Moreover, the tumor microenvironment is crucial and plays an active role in the metabolic adaptations and survival of cancer cells. Glucose transporters are overexpressed in cancer cells to increase glucose uptake. The glucose transporter 3 (GLUT3) is a high-affinity glucose transporter that is highly expressed in mammalian neurons. GLUT3 is also overexpressed in several malignant brain tumors. However, the role of GLUT3 in breast cancer brain metastasis remains unknown. The results of the present study demonstrated that GLUT3 is highly overexpressed in brain metastatic breast cancers and mediates glucose metabolic reprogramming. Furthermore, knockdown of cAMP-response element binding protein (CREB) could directly regulate GLUT3 expression in brain metastatic breast cancer cells. Notably, we verified and provided a novel role of GLUT3 in mediating glucose metabolism and assisting breast cancer cells to survive in the brain to promote brain metastasis.

scholarly journals BSCI-27. MELATONIN REDUCES MALIGNANCY OF BREAST CANCER BRAIN METASTATIC CELLS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i6-i6
Author(s):  
Beatriz Fernandez Gil ◽  
Katherine Rodriguez ◽  
Paula Schiapparelli ◽  
Carla Vazquez Ramos ◽  
Germaine Escames ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stage Iv ◽  
Metastatic Tumor ◽  
Breast Cancer Cell Lines ◽  
Small Subset ◽  
Tumor Initiating Cells ◽  
Stage Iv Breast Cancer ◽  
Breast Cancer Brain Metastasis ◽  
The Brain

Abstract Around fifteen to thirty percent of stage IV breast cancer metastasizes to the brain, severely decreasing the quality of life of these patients by causing neurological decline and eventually death. In metastatic cancers there is a small subset of cells in the primary tumor bulk called Metastatic Tumor Initiating Cells (MTICs) which are able to escape and produce a niche establishment at distal sites where they can quickly become resistant to surgery and radiation. Melatonin has shown an inhibitory role in the viability and invasiveness of breast cancer and in modulating the expression of proteins related to Breast Cancer Stem Cells (BCSCs). These findings suggest its potential anti-metastatic role in different breast cancer cell lines. In this study we aimed to evaluate the effects of melatonin treatment in vitro for breast cancer brain metastasis. The cell line MDA-BT was originally obtained from MDA-MB-231, passed through the rat’s heart and then isolated once engrafted as a tumor in the brain. After a dose response assay, cells were treated with melatonin at doses of 1500 and 3000 µM for 48hrs. Clonogenic assay, MTT, as well as a stem cell signature through RT-qPCR, including CD44, CD24 and ALDH1 markers, were performed to evaluate the malignancy of the MTICs. The results showed that melatonin at high doses impacts morphology, declines viability, reduces colony formation ability, and decreases stemness in MDA-BT cells. Therefore, our findings highlight melatonin as a relevant therapeutic candidate to target breast cancer brain metastases.

scholarly journals Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2838
Author(s):  
Shailendra K. Gautam ◽  
Ranjana K. Kanchan ◽  
Jawed A. Siddiqui ◽  
Shailendra K. Maurya ◽  
Sanchita Rauth ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cell Lines ◽  
Combination Treatment ◽  
Primary Tumor ◽  
Kinase Inhibitor ◽  
Orthotopic Model ◽  
Orthotopic Mouse Model ◽  
The Brain

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC.

scholarly journals BSCI-17. Targeting SIRPα as a therapeutic strategy for the treatment of breast cancer brain metastasis

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii4-iii4
Author(s):  
Elizabeth R Stirling ◽  
Steven M Bronson ◽  
William N Crowe ◽  
Adam Wilson ◽  
Mitra Kooshki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Immune Surveillance ◽  
Metastatic Breast ◽  
Fold Increase ◽  
Mitochondrial Respiratory Chain ◽  
Tumor Burden ◽  
Isotype Control ◽  
Breast Cancer Brain Metastasis

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the lack of druggable targets and an incidence of brain metastasis from the primary site of approximately 35%. There is no standard treatment for managing brain metastasis associated with TNBC; therefore, new strategies are urgently needed to overcome disease mortality. The CD47/SIRPα signaling pathway is implicated in tumor progression due to bypassing innate and adaptive immune surveillance. Most strategies targeting this pathway focus on targeting the receptor CD47; however, targeting SIRPα as a potential strategy to mitigate tumor burden remains understudied. Analysis of gene expression database shows that SIRPα expression is significantly elevated in invasive breast cancer when compared to primary. Furthermore, single-cell data indicates that SIRPα is expressed in basal epithelial cells in TNBC tumors aside from the myeloid compartment. Our immune staining against SIRPα in patient biopsies shows a five-fold increase in SIRPα expression in metastatic brain tumors compared to the primary lesions. Therefore, targeting SIRPα may be a new immunotherapeutic strategy to treat breast cancer brain metastases. Anti-SIRPα treatment of mice bearing brain metastatic 4T1br3 orthotopic tumors showed reduced tumor volume and tumor weight by over 50% compared to isotype control-treated mice. Furthermore, in a model of intracardial brain metastasis, treatment with SIRPα antibody was associated with a 60% increase in survival compared to isotype control-treated mice. RNA sequencing of tumors indicated that SIRPα blockade is associated with a reduction in genes linked to mitochondrial respiratory chain and increases in negative regulation of the cell cycle. Furthermore, in vitro SIRPα targeting enhanced the cell-mediated cytotoxicity of microglia against 4T1Br3 breast cancer cells. This suggests that SIRPα blockade may influence both tumor and innate immune cells to limit brain metastatic breast cancer growth and enhance survival.

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