scholarly journals Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jun Tian ◽  
Vivian Wang ◽  
Ni Wang ◽  
Baharak Khadang ◽  
Julien Boudreault ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
In Silico Analysis ◽  
Breast Tumorigenesis ◽  
Clinical Benefits ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Abstract Background Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors. Methods By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC. Results We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo. Conclusions Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment.

scholarly journals Overexpression of BQ323636.1 Modulated AR/IL-8/CXCR1 Axis to Confer Tamoxifen Resistance in ER-Positive Breast Cancer

Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 93
Author(s):  
Ho Tsoi ◽  
Ling Shi ◽  
Man-Hong Leung ◽  
Ellen P. S. Man ◽  
Zi-Qing So ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
In Silico Analysis ◽  
Luciferase Reporter ◽  
Androgen Response Element ◽  
Er Positive

NCOR2 is a co-repressor for estrogen receptor (ER) and androgen receptor (AR). Our group previously identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance via interference of NCOR2 repression on ER. Luciferase reporter assay showed BQ overexpression could enhance the transcriptional activity of androgen response element (ARE). We proposed that BQ employs both AR and ER to confer tamoxifen resistance. Through in silico analysis, we identified interleukin-8 (IL-8) as the sole ERE and ARE containing gene responsiveness to ER and AR activation. We confirmed that BQ overexpression enhanced the expression of IL-8 in ER+ve breast cancer cells, and AR inhibition reduced IL-8 expression in the BQ overexpressing cell lines, suggesting that AR was involved in the modulation of IL-8 expression by BQ. Moreover, we demonstrated that IL-8 could activate both AKT and ERK1/2 via CXCR1 to confer tamoxifen resistance. Targeting CXCR1/2 by a small inhibitor repertaxin reversed tamoxifen resistance of BQ overexpressing breast cancer cells in vitro and in vivo. In conclusion, BQ overexpression in ER+ve breast cancer can enhance IL-8 mediated signaling to modulate tamoxifen resistance. Targeting IL-8 signaling is a promising approach to overcome tamoxifen resistance in ER+ve breast cancer.

scholarly journals Centrosome amplification: a suspect in breast cancer and racial disparities

2017 ◽  
Vol 24 (9) ◽  
pp. T47-T64 ◽  
Author(s):  
Angela Ogden ◽  
Padmashree C G Rida ◽  
Ritu Aneja
Keyword(s):  
Breast Cancer ◽  
Centrosome Amplification ◽  
Breast Cancers ◽  
Breast Tumorigenesis ◽  
Breast Cancer Outcomes ◽  
Clinically Significant ◽  
Cellular Tolerance ◽  
Cellular Phenotypes

The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN) and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extantin vitro,in vivoand clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential ‘hit’ in multistep tumorigenesis, and in some others, non-tumorigenic. However,in vivodata are limited and primarily focus on PLK4 (which has CA-independent mechanisms by which it promotes aggressive cellular phenotypes).In vitrobreast cancer models suggest that CA can promote tumorigenesis in breast cancer cells in the setting of p53 loss or mutation, which can both trigger CA and promote cellular tolerance to its tendency to slow proliferation and induce aneuploidy. It is thus our perspective that CA is likely an early hit in multistep breast tumorigenesis that may sometimes be lost to preserve aggressive karyotypes acquired through centrosome clustering-mediated CIN, both numerical and structural. We also envision that the robust link between p53 and CA may underlie, to a considerable degree, racial health disparity in breast cancer outcomes. This question is clinically significant because, if it is true, then analysis of centrosomal profiles and administration of centrosome declustering drugs could prove highly efficacious in risk stratifying breast cancers and treating African American (AA) women with breast cancer.

scholarly journals DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

2018 ◽  
Vol 46 (2) ◽  
pp. 520-531 ◽  
Author(s):  
Yan Ding ◽  
Lanlan Shan ◽  
Wenqing Nai ◽  
Xiaojun Lin ◽  
Ling Zhou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Umbilical Vein ◽  
Vascular Endothelial Cell ◽  
Tube Formation ◽  
Vascular Endothelial

Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

scholarly journals Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast caner cells and osteoclasts

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Ming-Xuan Feng ◽  
Jian-Xin Hong ◽  
Qiang Wang ◽  
Yong-Yong Fan ◽  
Chi-Ting Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Resorption ◽  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Metastatic Breast ◽  
Osteoclast Formation ◽  
Migration And Invasion ◽  
Titanium Particle

Abstract Bone is the most common site of distant relapse in breast cancer, leading to severe complications which dramatically affect the patients’ quality of life. It is believed that the crosstalk between metastatic breast cancer cells and osteoclasts is critical for breast cancer-induced osteolysis. In this study, the effects of dihydroartemisinin (DHA) on osteoclast formation, bone resorption, osteoblast differentiation and mineralization were initially assessed in vitro, followed by further investigation in a titanium-particle-induced osteolysis model in vivo. Based on the proved inhibitory effect of DHA on osteolysis, DHA was further applied to MDA-MB-231 breast cancer-induced mouse osteolysis model, with the underlying molecular mechanisms further investigated. Here, we verified for the first time that DHA suppressed osteoclast differentiation, F-actin ring formation and bone resorption through suppressing AKT/SRC pathways, leading to the preventive effect of DHA on titanium-particle-induced osteolysis without affecting osteoblast function. More importantly, we demonstrated that DHA inhibited breast tumor-induced osteolysis through inhibiting the proliferation, migration and invasion of MDA-MB-231 cells via modulating AKT signaling pathway. In conclusion, DHA effectively inhibited osteoclastogenesis and prevented breast cancer-induced osteolysis.

scholarly journals COX-2 silencing enhances tamoxifen antitumor activity in breast cancer in vivo and in vitro

2014 ◽  
Vol 44 (4) ◽  
pp. 1385-1393 ◽  
Author(s):  
YE DU ◽  
AIPING SHI ◽  
BING HAN ◽  
SIJIE LI ◽  
DI WU ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Cox 2

scholarly journals Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish

2021 ◽  
Vol 22 (17) ◽  
pp. 9279
Author(s):  
Inés Martínez-Pena ◽  
Pablo Hurtado ◽  
Nuria Carmona-Ule ◽  
Carmen Abuín ◽  
Ana Belén Dávila-Ibáñez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Molecular Mechanisms ◽  
Zebrafish Embryo ◽  
Cancer Metastasis ◽  
Fluid Shear Stress ◽  
In Vivo Models

Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.

Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors

MedChemComm ◽  
2016 ◽  
Vol 7 (12) ◽  
pp. 2309-2327 ◽  
Author(s):  
Fatma A. Ragab ◽  
Helmi I. Heiba ◽  
Marwa G. El-Gazzar ◽  
Sahar M. Abou-Seri ◽  
Walaa A. El-Sabbagh ◽  
...  
Keyword(s):  
Paw Oedema ◽  
Analgesic Agents ◽  
Thiadiazole Derivatives ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Rat Paw ◽  
Cox 2 Inhibitors ◽  
Rat Paw Oedema

A novel series of thiadiazole derivatives were designed and synthesized for evaluation as selective COX-2 inhibitors in vitro and were investigated in vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats.

scholarly journals CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 129
Author(s):  
Huinan Qu ◽  
Da Qi ◽  
Xinqi Wang ◽  
Yuan Dong ◽  
Qiu Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Suppressor Gene ◽  
Binding Motif ◽  
Cancer Proliferation ◽  
In Vivo Experiments

Claudin 6 (CLDN6) was found to be a breast cancer suppressor gene, which is lowly expressed in breast cancer and inhibits breast cancer cell proliferation upon overexpression. However, the mechanism by which CLDN6 inhibits breast cancer proliferation is unclear. Here, we investigated this issue and elucidated the molecular mechanisms by which CLDN6 inhibits breast cancer proliferation. First, we verified that CLDN6 was lowly expressed in breast cancer tissues and that patients with lower CLDN6 expression had a worse prognosis. Next, we confirmed that CLDN6 inhibited breast cancer proliferation through in vitro and in vivo experiments. As for the mechanism, we found that CLDN6 inhibited c–MYC–mediated aerobic glycolysis based on a metabolomic analysis of CLDN6 affecting cellular lactate levels. CLDN6 interacted with a transcriptional co–activator with PDZ-binding motif (TAZ) and reduced the level of TAZ, thereby suppressing c–MYC transcription, which led to a reduction in glucose uptake and lactate production. Considered together, our results suggested that CLDN6 suppressed c–MYC–mediated aerobic glycolysis to inhibit the proliferation of breast cancer by TAZ, which indicated that CLDN6 acted as a novel regulator of aerobic glycolysis and provided a theoretical basis for CLDN6 as a biomarker of progression in breast cancer.

scholarly journals HOXB9 Promotes Laryngeal Squamous Cell Carcinoma Progression by Upregulating MMP12

2021 ◽  
Author(s):  
Chuanhui Sun ◽  
Peng Wang ◽  
Yujiang Chen ◽  
Qiuying Li ◽  
Hua Deng ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Histological Grade ◽  
Cell Cancer ◽  
In Vivo Studies ◽  
Migration And Invasion ◽  
High Level

Abstract Background：The HOX family transcription factor HOXB9 is a crucial element in the progression of various cancers. In the previous study conducted by the investigators, a drastically higher HOXB9 expression was reported in laryngeal squamous cell cancer (LSCC), when compared to adjacent normal laryngeal squamous tissues. Furthermore, a high level of HOXB9 was closely correlated with histological grade and overall survival in LSCC patients. However, the underlying molecular mechanisms have not been fully elucidated.Results: The present study explored the molecular mechanisms of HOXB9 in LSCC progression. Furthermore, the in vitro and in vivo studies revealed that the gene knockout of HOXB9 using the CRISPR/CAS9 system inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. Mechanistic studies in LSCC cell lines and human LSCC specimens demonstrated that HOXB9 promotes LSCC progression by directly upregulating the MMP12 expression at the level of its transcription.Conclusions: Collectively, the present study is the first to demonstrate the role of HOXB9 in the regulation of LSCC progression by enhancing the upregulation of MMP12.

scholarly journals Cross-talk between SIM2s and NFκB regulates cyclooxygenase 2 expression in breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Garhett L. Wyatt ◽  
Lyndsey S. Crump ◽  
Chloe M. Young ◽  
Veronica M. Wessells ◽  
Cole M. McQueen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclooxygenase 2 ◽  
Luciferase Reporter ◽  
Signaling Proteins ◽  
Dependent Manner ◽  
Mcf7 Cells ◽  
Human Breast Carcinomas ◽  
Cox 2

Abstract Background Breast cancer is a leading cause of cancer-related death for women in the USA. Thus, there is an increasing need to investigate novel prognostic markers and therapeutic methods. Inflammation raises challenges in treating and preventing the spread of breast cancer. Specifically, the nuclear factor kappa b (NFκB) pathway contributes to cancer progression by stimulating proliferation and preventing apoptosis. One target gene of this pathway is PTGS2, which encodes for cyclooxygenase 2 (COX-2) and is upregulated in 40% of human breast carcinomas. COX-2 is an enzyme involved in the production of prostaglandins, which mediate inflammation. Here, we investigate the effect of Singleminded-2s (SIM2s), a transcriptional tumor suppressor that is implicated in inhibition of tumor growth and metastasis, in regulating NFκB signaling and COX-2. Methods For in vitro experiments, reporter luciferase assays were utilized in MCF7 cells to investigate promoter activity of NFκB and SIM2. Real-time PCR, immunoblotting, immunohistochemistry, and chromatin immunoprecipitation assays were performed in SUM159 and MCF7 cells. For in vivo experiments, MCF10DCIS.COM cells stably expressing SIM2s-FLAG or shPTGS2 were injected into SCID mice and subsequent tumors harvested for immunostaining and analysis. Results Our results reveal that SIM2 attenuates the activation of NFκB as measured using NFκB-luciferase reporter assay. Furthermore, immunostaining of lysates from breast cancer cells overexpressing SIM2s showed reduction in various NFκB signaling proteins, as well as pAkt, whereas knockdown of SIM2 revealed increases in NFκB signaling proteins and pAkt. Additionally, we show that NFκB signaling can act in a reciprocal manner to decrease expression of SIM2s. Likewise, suppressing NFκB translocation in DCIS.COM cells increased SIM2s expression. We also found that NFκB/p65 represses SIM2 in a dose-dependent manner, and when NFκB is suppressed, the effect on the SIM2 is negated. Additionally, our ChIP analysis confirms that NFκB/p65 binds directly to SIM2 promoter site and that the NFκB sites in the SIM2 promoter are required for NFκB-mediated suppression of SIM2s. Finally, overexpression of SIM2s decreases PTGS2 in vitro, and COX-2 staining in vivo while decreasing PTGS2 and/or COX-2 activity results in re-expression of SIM2. Conclusion Our findings identify a novel role for SIM2s in NFκB signaling and COX-2 expression.

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