scholarly journals Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Yifeng Zheng ◽  
Pengxi Liu ◽  
Neng Wang ◽  
Shengqi Wang ◽  
Bowen Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Betulinic Acid ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Aerobic Glycolysis ◽  
Breast Cancer Metastasis ◽  
Related Proteins

Targeting aberrant metabolism is a promising strategy for inhibiting cancer growth and metastasis. Research is now geared towards investigating the inhibition of glycolysis for anticancer drug development. Betulinic acid (BA) has demonstrated potent anticancer activities in multiple malignancies. However, its regulatory effects on glycolysis and the underlying molecular mechanisms are still unclear. BA inhibited invasion and migration of highly aggressive breast cancer cells. Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins. In this study, glucose-regulated protein 78 (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis. Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK. Subsequent phosphorylation of eIF2α led to the inhibition of β-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis. Coimmunoprecipitation assay revealed that BA interrupted the binding between GRP78 and PERK, thereby initiating the glycolysis inhibition cascade. Finally, the lung colonization model validated that BA inhibited breast cancer metastasis in vivo, as well as suppressed the expression of aerobic glycolysis-related proteins. In conclusion, our study not only provided a promising drug for aerobic glycolysis inhibition but also revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during tumor metastasis.

scholarly journals NUPR1 Promotes the Proliferation and Migration of Breast Cancer Cells by Activating TFE3 Transcription to Induce Autophagy

2021 ◽  
Author(s):  
Heng Xiao ◽  
Jing Long ◽  
Xiang Chen ◽  
Mi-Duo Tan
Keyword(s):  
Breast Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Translocation Factor ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Related Proteins

Abstract Background: Breast cancer is a commonplace carcinoma in females. Recurrence and metastasis are the main problems affecting the survival rate of patients. The fundamental reason is the lack of understanding of the mechanism of breast cancer metastasis. This study aims to deliberate on the efficaciousness of Nuclear protein 1 (NUPR1)-mediated autophagy on breast cancer metastasis.Methods: The proliferation, migration and invasion ability of breast cancer cells were appraised by CCK-8, wound healing, and colony formation, as well as transwell assay. The relationship between NUPR1 and Translocation factor E3 (TFE3) was appraised by qPCR, western blot and ChIP. Migration-invasion-related proteins and autophagy-related proteins were appraised by western blot. The effects of NUPR1 on malignancy formation and metastasis were studied in vivo.Results: NUPR1 was upregulated in breast cancer cells and tissues. NUPR1 knockdown restrained the proliferation, migration and invasion of ZR-75-30 cells. Moreover, NUPR1 knockdown restrained malignancy formation and metastasis in vivo. Mechanically, NUPR1 promoted autophagy through activation of TFE3 transcription, thereby regulating the process of breast cancer metastasis.Conclusion: This paper elucidates the molecular mechanism of NUPR1 promoting breast cancer metastasis by activating autophagy through TFE3 signaling pathway, which provided biological basis for intervention of blocking distant metastasis.

scholarly journals Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Xinbo Qiao ◽  
Yixiao Zhang ◽  
Lisha Sun ◽  
Qingtian Ma ◽  
Jie Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Distant Metastasis ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Human Breast ◽  
Cell Conversion

Tumor metastasis remains the main cause of breast cancer-related deaths, especially delayed breast cancer distant metastasis. The current study assessed the frequency of CD44-/CD24- breast cancer cells in 576 tissue specimens for associations with clinicopathological features and metastasis and investigated the underlying molecular mechanisms. The results indicated that higher frequency (≥19.5%) of CD44-/CD24- cells was associated with delayed postoperative breast cancer metastasis. Furthermore, CD44-/CD24- triple negative breast cancer (TNBC) cells spontaneously converted into CD44+/CD24- cancer stem cells (CSCs) with properties similar to CD44+/CD24- CSCs from primary human breast cancer cells and parental TNBC cells in terms of stemness marker expression, self-renewal, differentiation, tumorigenicity and lung metastasis in vitro and in NOD/SCID mice. RNA sequencing identified several differentially expressed genes (DEGs) in newly converted CSCs and RHBDL2, one of the DEGs, expression was up-regulated. More importantly, RHBDL2 silencing inhibited the YAP1/USP31/NF-κB signaling and attenuated spontaneous CD44-/CD24- cell conversion into CSCs and their mammosphere formation. These findings suggest that the frequency of CD44-/CD24- tumor cells and RHBDL2 may be valuable for prognosis of delayed breast cancer metastasis, particularly for TNBC.

scholarly journals Biomechanical regulation of breast cancer metastasis and progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adrianne Spencer ◽  
Andrew D. Sligar ◽  
Daniel Chavarria ◽  
Jason Lee ◽  
Darshil Choksi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Mechanical Load ◽  
Breast Cancer Metastasis ◽  
Proliferation And Metastasis ◽  
Xenograft Models ◽  
Chemotherapeutic Treatment ◽  
Complex Signaling

AbstractPhysical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.

scholarly journals Mitochondrial Malic Enzyme 2 Promotes Breast Cancer Metastasis via Stabilizing HIF-1α Under Hypoxia

2021 ◽  
Author(s):  
Duo You ◽  
Danfeng Du ◽  
Xueke Zhao ◽  
Xinmin Li ◽  
Minfeng Ying ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
High Expression ◽  
Breast Cancer Patients ◽  
Cancer Model ◽  
Breast Cancer Model

Abstract Background: α-ketoglutarate (α-KG) is the substrate to hydoxylate collagen and hypoxia-inducible factor-1α (HIF-1α), which are important for cancer metastasis. Previous studies showed that upregulation of collagen prolyl 4-hydroxylase in breast cancer cells stabilizes HIF-1α via depleting α-KG in breast cancer cells. We propose that mitochondrial malate enzyme 2 (ME2) may also affect HIF-1α via modulating α-KG level in breast cancer cells. Methods: ME2 protein expression was evaluated by immunohistochemistry on 100 breast cancer patients and correlated with clinicopathological indicators. The effect of ME2 knockout on cancer metastasis was evaluated by an orthotopic breast cancer model. The effect of ME2 knockout or knockdown on the levels of α-KG and HIF-1α protein in breast cancer cell lines (4T1 and MDA-MB-231) was determined in vitro and in vivo.Results: The high expression of ME2 was observed in the human breast cancerous tissues compared to the matched precancerous tissues (P=0.000). The breast cancer patients with a high expression of ME2 had an inferior survival than the patients with low expression of ME2 (P=0.019). ME2 high expression in breast cancer tissues was also related with lymph node metastasis (P=0.016), pathological staging (P=0.033) and vascular cancer embolus (P=0.014). In a 4T1 orthotopic breast cancer model, ME2 knockout significantly inhibited lung metastasis. In the tumors formed by ME2 knockout 4T1 cells, α-KG level significantly increased, collagen hydroxylation level did not change significantly, but HIF-1α protein level significantly decreased, in comparison to control. In cell culture, ME2 knockout or knockdown cells demonstrated a significantly higher α-KG level but significantly lower HIF-1α protein level than control cells under hypoxia. Exogenous malate and α-KG exerted similar effect on HIF-1α in breast cancer cells to ME2 knockout or knockdown. Treatment with malate significantly decreased 4T1 breast cancer lung metastasis. ME2 expression was associated with HIF-1α level in human breast cancer samples (P=0.027).Conclusion: We provide evidence that upregulation of ME2 is associated with a poor prognosis of breast cancer patients and propose a mechanistic understanding of a link between ME2 and breast cancer metastasis.

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.

miR-214 inhibits epithelial–mesenchymal transition of breast cancer cells via downregulation of RNF8

2019 ◽  
Vol 51 (8) ◽  
pp. 791-798 ◽  
Author(s):  
Lu Min ◽  
Chuanyang Liu ◽  
Jingyu Kuang ◽  
Xiaomin Wu ◽  
Lingyun Zhu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Proliferation And Invasion

Abstract MicroRNAs (miRNAs) are a class of endogenous noncoding genes that regulate gene expression at the posttranscriptional level. In recent decades, miRNAs have been reported to play important roles in tumor growth and metastasis, while some reported functions of a specific miRNA in tumorigenesis are contradictory. In this study, we reevaluated the role of miR-214, which has been reported to serve as an oncogene or anti-oncogene in breast cancer metastasis. We found that miR-214 inhibited breast cancer via targeting RNF8, a newly identified regulator that could promote epithelial–mesenchymal transition (EMT). Specifically, the survival rate of breast cancer patients was positively correlated with miR-214 levels and negatively correlated with RNF8 expression. The overexpression of miR-214 inhibited cell proliferation and invasion of breast cancer, while suppression of miR-214 by chemically modified antagomir enhanced the proliferation and invasion of breast cancer cells. Furthermore, miR-214 could modulate the EMT process via downregulating RNF8. To our knowledge, this is the first report that reveals the role of the miR-214–RNF8 axis in EMT, and our results demonstrate a novel mechanism for miR-214 acting as a tumor suppressor through the regulation of EMT.

scholarly journals The long non-coding RNA ET-20 mediates EMT by impairing desmosomes in breast cancer cells

2021 ◽  
Author(s):  
Meera Saxena ◽  
Mizue Hisano ◽  
Melanie Neutzner ◽  
Maren Diepenbruck ◽  
Robert Ivanek ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Matrix Protein ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Invasive Human Breast Cancer

The vast majority of breast cancer-associated deaths are due to metastatic spread of cancer cells, a process aided by epithelial-mesenchymal transition (EMT). Mounting evidence has indicated that long non-coding RNAs (lncRNAs) also contribute to tumor progression. We report the identification of 114 novel lncRNAs that change their expression during TGFβ-induced EMT in murine breast cancer cells (referred to as EMT-associated transcripts; ETs). Of these, the ET-20 gene localizes in antisense orientation within the Tenascin C (Tnc) gene locus. Tnc is an extra-cellular matrix protein which is critical for EMT and metastasis formation. Both ET-20 and Tnc are regulated by the EMT master transcription factor Sox4. Notably, ablation of ET-20 lncRNA effectively blocks Tnc expression and with it EMT. Mechanistically, ET-20 interacts with desmosomal proteins, thereby impairing epithelial desmosomes and promoting EMT. A short transcript variant of ET-20 is found upregulated in invasive human breast cancer cell lines where it also promotes EMT. Targeting ET-20 appears a therapeutically attractive lead to restrain EMT and breast cancer metastasis in addition to its potential utility as a biomarker for invasive breast cancer.

scholarly journals Compressive Stress Enhances Invasive Phenotype of Breast Cancer Cells via Piezo1 Activation

2019 ◽  
Author(s):  
Mingzhi Luo ◽  
Kenneth KY Ho ◽  
Zhaowen Tong ◽  
Linhong Deng ◽  
Allen Liu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Compressive Stress ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Calcium Influx ◽  
Breast Cancer Metastasis ◽  
Matrix Degradation ◽  
Apical Side ◽  
Actin Protrusions

Abstract Uncontrolled growth in solid tumor generates compressive stress that drives cancer cells into invasive phenotypes, but little is known about how such stress affects the invasion and matrix degradation of cancer cells and the underlying mechanisms. Here we show that compressive stress enhanced invasion and matrix degradation of breast cancer cells. We further identified Piezo1 as the putative mechanosensitive cellular component that transmits compressive stress to induce calcium influx, which in turn activate Src/ERK signaling. Interestingly, we observed actin protrusions with matrix degradation ability on the apical side of the cells. Furthermore, we demonstrate that Piezo1 channels were partially localized in caveolae, and reduction of caveolin-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress. Taken together, our data indicate that mechanical compressive stress activates Piezo1 channels to mediate enhanced cancer cell invasion and matrix degradation that may be a critical mechanotransduction pathway during, and potentially a novel therapeutic target for, breast cancer metastasis.

scholarly journals Biomechanical Regulation of Breast Cancer Metastasis and Progression

2020 ◽  
Author(s):  
Adrianne Spencer ◽  
Andrew D. Sligar ◽  
Daniel Chavarria ◽  
Jason Lee ◽  
Darshil Choksi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Mechanical Load ◽  
Breast Cancer Metastasis ◽  
Proliferation And Metastasis ◽  
Xenograft Models ◽  
Chemotherapeutic Treatment ◽  
Complex Signaling

AbstractPhysical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.

Sign in / Sign up

Export Citation Format

Share Document