scholarly journals Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3003
Author(s):  
Di Zhang ◽  
Sadahiro Iwabuchi ◽  
Tomohisa Baba ◽  
Shin-ichi Hashimoto ◽  
Naofumi Mukaida ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Bone Metastasis ◽  
Cancer Metastasis ◽  
High Growth ◽  
Breast Cancer Metastasis ◽  
Tumor Formation ◽  
Bone Microenvironment ◽  
Tnbc Cell

Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment.

scholarly journals 4543 Glucocorticoid Receptors are essential effectors of TGFβ signaling in Triple Negative Breast Cancer

2020 ◽  
Vol 4 (s1) ◽  
pp. 7-8
Author(s):  
Carlos Jesus Perez Kerkvliet ◽  
Amy R Dwyer ◽  
Caroline Diep ◽  
Robert Oakley ◽  
Christopher Liddle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
P38 Mapk ◽  
Cell Biology ◽  
Glucocorticoid Receptors ◽  
Cancer Metastasis ◽  
Target Genes ◽  
Mapk Signaling ◽  
Breast Cancer Metastasis ◽  
Tnbc Cell

OBJECTIVES/GOALS: The glucocorticoid receptor (GR) is a ubiquitous steroid hormone receptor that is emerging as a mediator of breast cancer metastasis. We aim to better understand the biology associated with phospho-GR species in TNBC and their contribution to tumor progression. METHODS/STUDY POPULATION: To better understand how p-S134 GR may impact TNBC cell biology, we probed GR regulation by soluble factors that are rich within the tumor microenvironment (TME), such as TGFβ. TNBC cells harboring endogenous wild-type or S134A-GR species were created by CRISPR/Cas knock-in and subjected to in vitro assays of advanced cancer behavior. RNA-Seq was employed to identify pS134-GR target genes that are uniquely regulated by TGFβ in the absence of exogenously added GR ligands. Direct regulation of selected TGFβ-induced pS134-GR target genes was validated accordingly. Bioinformatics tools were used to probe publicly available TNBC patient data sets for expression of a pS134-GR 24-gene signature. RESULTS/ANTICIPATED RESULTS: In the absence of GR ligands, GR is transcriptionally activated via p38-MAPK-dependent phosphorylation of Ser134 upon exposure of TNBC cells to TME-derived agents (TGFβ, HGF). The ligand-independent pS134-GR transcriptome primarily encompasses gene sets associated with TNBC cell survival and migration/invasion. Accordingly, pS134-GR was essential for TGFβ-induced TNBC cell migration, anchorage-independent growth in soft-agar, and tumorsphere formation, an in vitro readout of breast cancer stemness properties. Finally, a 24-gene pSer134-GR-dependent signature induced by TGFβ1 predicts shortened survival in breast cancer. We expect to find similar results using an in-house tissue microarray. DISCUSSION/SIGNIFICANCE OF IMPACT: Phospho-S134-GR is a critical downstream mediator of p38 MAPK signaling and TNBC migration, survival, and stemness properties. Our studies define GR as a required effector of TGFβ1 signaling and nominate pS134-GR as a biomarker of elevated risk of breast cancer dissemination.

scholarly journals Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elizabeth Garcia ◽  
Ismat Luna ◽  
Kaya L. Persad ◽  
Kate Agopsowicz ◽  
David A. Jay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Breast Cancer Metastasis ◽  
Boyden Chamber ◽  
Invasive Potential ◽  
Mesenchymal Transition ◽  
Tnbc Cell

AbstractInvasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues’ ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.

scholarly journals Embracing Mechanobiology in Next Generation Organ-On-A-Chip Models of Bone Metastasis

2021 ◽  
Vol 3 ◽  
Author(s):  
Ellen E. Slay ◽  
Fiona C. Meldrum ◽  
Virginia Pensabene ◽  
Mahetab H. Amer
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Vital Role ◽  
Next Generation ◽  
Organ On A Chip ◽  
Cell Matrix Interactions

Bone metastasis in breast cancer is associated with high mortality. Biomechanical cues presented by the extracellular matrix play a vital role in driving cancer metastasis. The lack of in vitro models that recapitulate the mechanical aspects of the in vivo microenvironment hinders the development of novel targeted therapies. Organ-on-a-chip (OOAC) platforms have recently emerged as a new generation of in vitro models that can mimic cell-cell interactions, enable control over fluid flow and allow the introduction of mechanical cues. Biomaterials used within OOAC platforms can determine the physical microenvironment that cells reside in and affect their behavior, adhesion, and localization. Refining the design of OOAC platforms to recreate microenvironmental regulation of metastasis and probe cell-matrix interactions will advance our understanding of breast cancer metastasis and support the development of next-generation metastasis-on-a-chip platforms. In this mini-review, we discuss the role of mechanobiology on the behavior of breast cancer and bone-residing cells, summarize the current capabilities of OOAC platforms for modeling breast cancer metastasis to bone, and highlight design opportunities offered by the incorporation of mechanobiological cues in these platforms.

scholarly journals Reduced RhoA expression enhances breast cancer metastasis with a concomitant increase in CCR5 and CXCR4 chemokines signaling

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gardiyawasam Kalpana ◽  
Christopher Figy ◽  
Miranda Yeung ◽  
Kam C. Yeung
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Tumor Formation ◽  
Receptor Expression ◽  
Mechanistic Study ◽  
Metastasis Suppressor ◽  
Primary Tumors

Abstract The role of RhoA GTPases in breast cancer tumorigenesis and metastasis is unclear. Early studies within which mutations in RhoA were designed based on cancer-associated mutations in Ras supported an oncogene role for RhoA. However, recent whole-genome sequencing studies of cancers raised the possibility that RhoA may have a tumor suppression function. Here, using a syngeneic triple negative breast cancer murine model we investigated the physiological effects of reduced RhoA expression on breast cancer tumorigenesis and metastasis. RhoA knockdown had no effect on primary tumor formation and tumor proliferation, concurring with our in vitro findings where reduced RhoA had no effect on breast cancer cell proliferation and clonogenic growth. In contrast, primary tumors with RhoA knockdown efficiently invaded sentinel lymph nodes and significantly metastasized to lungs compared to control tumors. Mechanistically, the current study demonstrated that this is achieved by promoting a pro-tumor microenvironment, with increased cancer-associated fibroblasts and macrophage infiltration, and by modulating the CCL5-CCR5 and CXCL12-CXCR4 chemokine axes in the primary tumor. To our knowledge, this is the first such mechanistic study in breast cancer showing the ability of RhoA to suppress chemokine receptor expression in breast tumor cells. Our work suggests a physiological lung and lymph node metastasis suppressor role for RhoA GTPase in breast cancer.

scholarly journals Obesity-Activated Lung Stomal Cells Promote Myeloid-Lineage Cell Accumulation and Breast Cancer Metastasis

2020 ◽  
Author(s):  
Lauren E. Hillers-Ziemer ◽  
Abbey E. Williams ◽  
Amanda Janquart ◽  
Caitlin Grogan ◽  
Victoria Thompson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stromal Cells ◽  
Cancer Metastasis ◽  
Lung Metastases ◽  
Breast Cancer Metastasis ◽  
Tumor Formation ◽  
Obese Mice ◽  
Myeloid Lineage ◽  
Primary Tumors

SUMMARYObesity is correlated with increased incidence of breast cancer metastasis, however the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obesity mouse model, obesity enhanced lung metastases in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of pre-metastatic niches formed by primary tumors. Lung stromal cells isolated from obese non-tumor-bearing mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers, and TGFβ1. Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to CSF2 expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive for metastatic growth.

scholarly journals Obesity-Activated Lung Stromal Cells Promote Myeloid Lineage Cell Accumulation and Breast Cancer Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1005
Author(s):  
Lauren E. Hillers-Ziemer ◽  
Abbey E. Williams ◽  
Amanda Janquart ◽  
Caitlin Grogan ◽  
Victoria Thompson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stromal Cells ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Tumor Formation ◽  
Obese Mouse ◽  
Obese Mice ◽  
Myeloid Lineage ◽  
Primary Tumors

Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.

scholarly journals Three-Dimensional In Vitro Hydro- and Cryogel-Based Cell-Culture Models for the Study of Breast-Cancer Metastasis to Bone

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 292 ◽  
Author(s):  
Laura Bray ◽  
Constanze Secker ◽  
Berline Murekatete ◽  
Jana Sievers ◽  
Marcus Binner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Cell Function ◽  
Three Dimensional ◽  
Breast Cancer Metastasis ◽  
In Vitro Models ◽  
Cellular Migration ◽  
Breast Tumor Tissue ◽  
Culture Models

Bone is the most common site for breast-cancer invasion and metastasis, and it causes severe morbidity and mortality. A greater understanding of the mechanisms leading to bone-specific metastasis could improve therapeutic strategies and thus improve patient survival. While three-dimensional in vitro culture models provide valuable tools to investigate distinct heterocellular and environmental interactions, sophisticated organ-specific metastasis models are lacking. Previous models used to investigate breast-to-bone metastasis have relied on 2.5D or singular-scaffold methods, constraining the in situ mimicry of in vitro models. Glycosaminoglycan-based gels have demonstrated outstanding potential for tumor-engineering applications. Here, we developed advanced biphasic in vitro microenvironments that mimic breast-tumor tissue (MCF-7 and MDA-MB-231 in a hydrogel) spatially separated with a mineralized bone construct (human primary osteoblasts in a cryogel). These models allow distinct advantages over former models due to the ability to observe and manipulate cellular migration towards a bone construct. The gels allow for the binding of adhesion-mediating peptides and controlled release of signaling molecules. Moreover, mechanical and architectural properties can be tuned to manipulate cell function. These results demonstrate the utility of these biomimetic microenvironment models to investigate heterotypic cell–cell and cell–matrix communications in cancer migration to bone.

BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13002-e13002
Author(s):  
Yinghuan Cen ◽  
Chang Gong ◽  
Jun Li ◽  
Gehao Liang ◽  
Zihao Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Qrt Pcr ◽  
Metastatic Sites

e13002 Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.

scholarly journals EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Deepika Neelakantan ◽  
Hengbo Zhou ◽  
Michael U. J. Oliphant ◽  
Xiaomei Zhang ◽  
Lukas M. Simon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Tumour Cells ◽  
Human Breast ◽  
Breast Tumours ◽  
Cancer Models ◽  
Pdx Models

Abstract Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation.

POU1F1 transcription factor promotes breast cancer metastasis via recruitment and polarization of macrophages

2019 ◽  
Vol 249 (3) ◽  
pp. 381-394 ◽  
Author(s):  
Samuel Seoane ◽  
Anxo Martinez‐Ordoñez ◽  
Noemi Eiro ◽  
Pablo Cabezas‐Sainz ◽  
Lucia Garcia‐Caballero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis
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