scholarly journals Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Junko Tsuchida ◽  
Masayuki Nagahashi ◽  
Kazuaki Takabe ◽  
Toshifumi Wakai
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Clinical Importance ◽  
Breast Cancer Metastasis ◽  
Lipid Mediator ◽  
Breast Cancer Patients ◽  
Cellular Functions ◽  
Sphingosine 1 Phosphate ◽  
Underlying Mechanisms

Breast cancer metastasizes to lymph nodes or other organs, which determine the prognosis of patients. It is difficult to cure the breast cancer patients with distant metastasis due to resistance to drug therapies. Elucidating the underlying mechanisms of breast cancer metastasis and drug resistance is expected to provide new therapeutic targets. Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive lipid mediator that regulates many cellular functions, including proliferation, migration, survival, angiogenesis/lymphangiogenesis, and immune responses. S1P is formed in cells by sphingosine kinases and released from them, which acts in an autocrine, paracrine, and/or endocrine manner. S1P in extracellular space, such as interstitial fluid, interacts with components in the tumor microenvironment, which may be important for metastasis. Importantly, recent translational research has demonstrated an association between S1P levels in breast cancer patients and clinical outcomes, highlighting the clinical importance of S1P in breast cancer. We suggest that S1P is one of the key molecules to overcome the resistance to the drug therapies, such as hormonal therapy, anti-HER2 therapy, or chemotherapy, all of which are crucial aspects of a breast cancer treatment.

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.

Serum ANGPTL2 Levels Reflect Clinical Features of Breast Cancer Patients: Implications for the Pathogenesis of Breast Cancer Metastasis

2014 ◽  
Vol 29 (3) ◽  
pp. 239-245 ◽  
Author(s):  
Motoyoshi Endo ◽  
Yutaka Yamamoto ◽  
Masahiro Nakano ◽  
Tetsuro Masuda ◽  
Haruki Odagiri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Features ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Ductal Carcinoma ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Patients

Introduction Breast cancer is a leading cause of cancer-related death in women worldwide, and its metastasis is a major cause of disease mortality. Therefore, identification of the mechanisms underlying breast cancer metastasis is crucial for the development of therapeutic and diagnostic strategies. Our recent study of immunodeficient female mice transplanted with MDA-MB231 breast cancer cells demonstrated that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) accelerates metastasis through both increasing tumor cell migration in an autocrine/paracrine manner, and enhancing tumor angiogenesis. To determine whether ANGPTL2 contributes to its clinical pathogenesis, we asked whether serum ANGPTL2 levels reflect the clinical features of breast cancer progression. Methods We monitored the levels of secreted ANGPTL2 in supernatants of cultured proliferating MDA-MB231 cells. We also determined whether the circulating ANGPTL2 levels were positively correlated with cancer progression in an in vivo breast cancer xenograft model using MDA-MB231 cells. Finally, we investigated whether serum ANGPTL2 levels were associated with clinical features in breast cancer patients. Results Both in vitro and in vivo experiments showed that the levels of ANGPTL2 secreted from breast cancer cells increased with cell proliferation and cancer progression. Serum ANGPTL2 levels in patients with metastatic breast cancer were significantly higher than those in healthy subjects or in patients with ductal carcinoma in situ or non-metastatic invasive ductal carcinoma. Serum ANGPTL2 levels in patients negative for estrogen receptors and progesterone receptors, particularly triple-negative cases, reflected histological grades. Conclusions These findings suggest that serum ANGPTL2 levels in breast cancer patients could represent a potential marker of breast cancer metastasis.

Factors associated with mortality after breast cancer metastasis.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 174-174
Author(s):  
S. Y. Jung ◽  
M. Q. Rosenzweig ◽  
S. M. Sereika ◽  
F. Linkov ◽  
A. Brufsky ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Factors ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Cox Regression ◽  
Metastatic Breast ◽  
Breast Cancer Metastasis ◽  
Her2 Status ◽  
Breast Cancer Patients

174 Background: It is generally accepted that patients with breast cancer metastases have poor survival. Metastatic breast cancer patients can be considered a heterogeneous population with a varied clinical course, which underscores the need for accurate prediction of survival based on prognostic factors. The purpose of the present study was to identify factors related to survival in breast cancer patients after diagnosis with metastatic disease. Methods: A total of 557 patients with breast cancer metastasis diagnosis seen at one large urban practice have been followed up between January 1, 1999 and June 30, 2008. Demographic, tumor characteristics, clinical factors as predictors of survival were analyzed using Cox regression model. Results: The median survival length was 40 months (range 1-114 months) with 269 (48.3%) alive and 288 (51.7%) dead. This study demonstrated that hypertension, estrogen receptor (ER) and/or progesterone receptor (PR) status, human epidermal growth factor receptor-2 (HER2) status, number of metastatic sites, and body mass index (BMI) at diagnosis with metastatic breast cancer were the most relevant prognostic factors for survival after metastasis. Conclusions: Findings of this study may form a foundation for the corpus of knowledge explaining the outcome differences in treatment of patients with metastatic breast cancer, potentially helping to create tailored counseling and personalized treatment approaches for this vulnerable group. [Table: see text]

Metformin May Block the Way Breast Cancer Metastasis: A Meta-analysis and Mechanism Review

2020 ◽  
Author(s):  
Ming Yang ◽  
Yueyuan Wang ◽  
Zhihao Zhang ◽  
Jingyu Peng ◽  
Xiao Xie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Distant Metastasis ◽  
Retrospective Cohort ◽  
Cancer Metastasis ◽  
Meta Analysis ◽  
Random Effect ◽  
Breast Cancer Metastasis ◽  
Cochrane Library ◽  
Breast Cancer Patients

Abstract Background Metformin, which is cheap and easy to get, is a first-line anti-hyperglycemia drug. Recently, its anti-tumor effect has been revealed. Here we performed a meta-analysis to summarize previous studies and a narrative review to gather the mechanisms involved in the potential relationship. Methods We searched related articles in database of Pubmed, EMbase, Web of science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), the Wanfang and Sinomed and obtained 8 clinic trials that investigated the connection between metformin and breast cancer metastasis, containing 2 randomized controlled trials (RCTs) and 6 retrospective cohort studies. We evaluated each retrospective cohort study by Newcastle-Ottawa Scale (NOS), while RCT by Chcorane Risk of Bias tool. Pooled hazard ratios (HRs), risk ratios (RRs) and we calculated associated 95% confidence intervals (CIs) with a random-effect, generic inverse variance method. We also collected the possible mechanisms of cancer metastasis inhibition from metformin. Results A total of 8 studies containing 13919 breast cancer patients without distant metastasis before they got anticancer treatment. The result showed that adjuvant metformin in treatment of local breast cancer facilitated to suppress metastasis (HR = 0.69, 95% CI = 0.57–0.82, p < 0.0001, I2 = 0%), and the result was consistent with the subgroup of breast cancer patients with type 2 diabetes mellitus (T2DM) (HR = 0.68, 95% CI = 0.57–0.82, p < 0.0001, I2 = 0%). Conclusion The meta-analysis suggested metformin might repress the metastasis and be benefit to distant metastasis-free survival (DMFS) when added to systemic breast cancer therapy, supporting anti-tumor effects of metformin on breast cancer.

scholarly journals Paradoxical Association of Postoperative Plasma Sphingosine-1-Phosphate with Breast Cancer Aggressiveness and Chemotherapy

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Rajesh Ramanathan ◽  
Ali Raza ◽  
Jamie Sturgill ◽  
Debra Lyon ◽  
Jessica Young ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Therapy ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Regulatory Function ◽  
Lipid Mediator ◽  
Breast Cancer Patients ◽  
Cancer Aggressiveness ◽  
Sphingosine 1 Phosphate ◽  
Healthy Control

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that has been shown to serve an important regulatory function in breast cancer progression. This study analyzes plasma S1P levels in breast cancer patients undergoing adjuvant therapy as compared to healthy control volunteers. 452 plasma S1P samples among 158 breast cancer patients, along with 20 healthy control volunteers, were analyzed. Mean S1P levels did not significantly differ between cancer patients and controls. Smoking was associated with higher S1P levels in cancer patients. Baseline S1P levels had weak inverse correlation with levels of the inflammatory mediator interleukin- (IL-) 17 and CCL-2 and positive correlation with tumor necrosis factor alpha (TNF-α). Midpoint S1P levels during adjuvant therapy were lower than baseline, with near return to baseline after completion, indicating a relationship between chemotherapy and circulating S1P. While stage of disease did not correlate with plasma S1P levels, they were lower among patients with Her2-enriched and triple-negative breast cancer as compared to luminal-type breast cancer. Plasma S1P levels are paradoxically suppressed in aggressive breast cancer and during adjuvant chemotherapy, which raises the possibility that postoperative plasma S1P levels do not reflect S1P secretion from resected breast cancer.

scholarly journals The roles of long noncoding RNAs in breast cancer metastasis

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Lingxia Liu ◽  
Yu Zhang ◽  
Jun Lu
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Noncoding Rnas ◽  
Breast Cancer Metastasis ◽  
Long Noncoding Rnas ◽  
Breast Cancer Patients ◽  
Breast Cancer Invasion ◽  
Future Challenges

Abstract Breast cancer is the most significant threat to female health. Breast cancer metastasis is the major cause of mortality in breast cancer patients. To fully unravel the molecular mechanisms that underlie the breast cancer cell metastasis is critical for developing strategies to improve survival and prognosis in breast cancer patients. Recent studies have revealed that the long noncoding RNAs (lncRNAs) are involved in breast cancer metastasis through a variety of molecule mechanisms, though the precise functional details of these lncRNAs are yet to be clarified. In the present review, we focus on the functions of lncRNAs in breast cancer invasion and metastasis, with particular emphasis on the functional properties, the regulatory factors, the therapeutic promise, as well as the future challenges in studying these lncRNA.

scholarly journals Adipocyte-Derived Leptin Promotes PAI-1-Mediated Breast Cancer Metastasis in a STAT3/miR-34a Dependent Manner

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3864
Author(s):  
Si-Jing Li ◽  
Xiao-Hui Wei ◽  
Xiao-Man Zhan ◽  
Jin-Yong He ◽  
Yu-Qi Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Loss Of Function ◽  
Pai 1

The crosstalk between cancer cells and adipocytes is critical for breast cancer progression. However, the molecular mechanisms underlying these interactions have not been fully characterized. In the present study, plasminogen activator inhibitor-1 (PAI-1) was found to be a critical effector of the metastatic behavior of breast cancer cells upon adipocyte coculture. Loss-of-function studies indicated that silencing PAI-1 suppressed cancer cell migration. Furthermore, we found that PAI-1 was closely related to the epithelial-mesenchymal transition (EMT) process in breast cancer patients. A loss-of-function study and a mammary orthotopic implantation metastasis model showed that PAI-1 promoted breast cancer metastasis by affecting the EMT process. In addition, we revealed that leptin/OBR mediated the regulation of PAI-1 through the interactions between adipocytes and breast cancer cells. Mechanistically, we elucidated that leptin/OBR further activated STAT3 to promote PAI-1 expression via miR-34a–dependent and miR-34a–independent mechanisms in breast cancer cells. In conclusion, our study suggests that targeting PAI-1 and interfering with its upstream regulators may benefit breast cancer patients.

scholarly journals Latent Cytomegalovirus Infection in Female Mice Increases Breast Cancer Metastasis

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 447 ◽  
Author(s):  
Zelei Yang ◽  
Xiaoyun Tang ◽  
Guanmin Meng ◽  
Matthew Benesch ◽  
Martina Mackova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Lung Metastases ◽  
Breast Tumors ◽  
Breast Cancer Metastasis ◽  
Negative Control ◽  
Breast Cancer Patients ◽  
Mcmv Infection ◽  
Latently Infected

Cytomegalovirus (CMV) infects 40–70% of women, but infection has been reported in >95% of breast cancer patients. We investigated the consequences of these observations by infecting mice with mCMV or a negative control medium for 4 days, 11 days or 10 weeks to establish active, intermediate or latent infections, respectively. Syngeneic 4T1 or E0771 breast cancer cells were then injected into a mammary fat pad of BALB/c or C57BL/6 mice, respectively. Infection did not affect tumor growth in these conditions, but latently infected BALB/c mice developed more lung metastases. The latent mCMV infection of MMTV-PyVT mice, which develop spontaneous breast tumors, also did not affect the number or sizes of breast tumors. However, there were more tumors that were multilobed with greater blood content, which had enhanced vasculature and decreased collagen content. Most significantly, mCMV infection also increased the number and size of lung metastases, which showed a higher cell proliferation. Viral DNA was detected in breast tumors and lung nodules although viral mRNA was not. These novel results have important clinical implications since an increased metastasis is prognostic of decreased survival. This work provides evidence that treating or preventing HCMV infections may increase the life expectancy of breast cancer patients by decreasing metastasis.

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