scholarly journals Targeting prooxidant MnSOD effect inhibits triple-negative breast cancer (TNBC) progression and M2 macrophage functions under the oncogenic stress

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Aushia Tanzih Al Haq ◽  
Hong-Yu Tseng ◽  
Li-Mei Chen ◽  
Chien-Chia Wang ◽  
Hsin-Ling Hsu
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
M2 Macrophage ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Mitochondrial Superoxide ◽  
Mitochondrial Ros ◽  
Immunosuppressive Tumor Microenvironment ◽  
The Impact

AbstractTriple-negative breast cancer (TNBC) has been shown with high mitochondrial oxidative phosphorylation and production of reactive oxygen species (ROS). MnSOD (SOD2) is a mitochondrial antioxidant defense that has been implicated in inhibition of human malignancies. However, the impact of MnSOD on immunosuppressive macrophage functions and TNBC aggressiveness has never been explored. We found here that SOD2high is primarily observed in the aggressive subtypes of HER2(+) breast cancers and TNBCs patients. Further analyses demonstrated that the oncoprotein multiple copies in T-cell malignancy-1 (MCT-1 or MCTS1) induces mitochondrial superoxide dismutase (MnSOD) in TNBC cells by stabilizing the transcription factor Nrf2. SOD2high/MCTS1high expression correlates with a poor prognosis in breast cancer patients. MnSOD in TNBC cells functions as a prooxidant peroxidase that increases mitochondrial ROS (mROS) and adaptation to oxidative stress under the oncogenic effect. Interleukin-6 (IL-6) in the MCT-1 pathway elevates Nrf2/MnSOD and mROS levels. Knockdown of MnSOD inhibits TNBC cell invasion, breast cancer stem cells (BCSCs), mROS, and IL-6 excretion promoted by MCT-1. TNBC cells deficient in MnSOD prevent the polarization and chemotaxis of M2 macrophages but improve the ability of M1 macrophages to engulf cancer cells. Quenching mROS with MitoQ, a mitochondria-targeted non-metal-based antioxidant MnSOD mimics, effectively suppresses BCSCs and M2 macrophage invasion exacerbated by MnSOD and MCT-1. Consistently, silencing MnSOD impedes TNBC progression and intratumoral M2 macrophage infiltration. We revealed a novel stratagem for TNBC management involving targeting the MCT-1 oncogene-induced mitochondrial prooxidant MnSOD pathway, which prevents the development of an immunosuppressive tumor microenvironment.

scholarly journals M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Fang Dong ◽  
Shengnan Ruan ◽  
Jinlong Wang ◽  
Yun Xia ◽  
Kehao Le ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Triple Negative Breast Cancer ◽  
Noncoding Rna ◽  
Triple Negative ◽  
M2 Macrophage ◽  
Breast Cancers ◽  
The Impact

Abstract As a common female malignancy, triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancers (BC). This study further studied the role of long noncoding RNA (lncRNA) prostate cancer-associated transcript 6 (PCAT6) in TNBC. Functional assays, including EdU, wound healing, transwell, and immunofluorescence staining, revealed the effect of PCAT6 on cell proliferation, migration, and EMT process. The tube-formation assay disclosed the function of PCAT6 on angiogenesis. In vivo assays were also established to explore the impact of PCAT6 on tumor growth and microangiogenesis. The results revealed that PCAT6 boosted TNBC cell proliferation, migration, and angiogenesis both in vitro and in vivo. Then, this study unveiled that M2 macrophage secreted VEGF to stimulate the upregulation of PCAT6, thus promoting angiogenesis in TNBC. Next, through bioinformatics analysis and mechanism assays, we identified that PCAT6 positively regulated VEGFR2 expression via ceRNA pattern and then participated in VEGFR/AKT/mTOR signaling pathway to accelerate angiogenesis. Moreover, PCAT6 bound USP14, a deubiquitinase, to induce the deubiquitination of VEGFR2. On the whole, M2 macrophage-induced upregulation of PCAT6 facilitates TNBC tumorigenesis through modulation of VEGFR2 expression via ceRNA and deubiquitination patterns.

scholarly journals PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

Breast Care ◽  
2020 ◽  
pp. 1-9
Author(s):  
Rudolf Napieralski ◽  
Gabriele Schricker ◽  
Gert Auer ◽  
Michaela Aubele ◽  
Jonathan Perkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Predictive Value ◽  
Untreated Patient ◽  
Triple Negative ◽  
Statistical Significance ◽  
Breast Cancer Patients ◽  
The Impact

<b><i>Background:</i></b> PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort. <b><i>Material and Methods:</i></b> The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed. <b><i>Results:</i></b> The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; <i>p</i> = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR &#x3e;2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; <i>p</i> = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; <i>p</i> = 0.014). <b><i>Conclusion:</i></b> In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.

scholarly journals Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 259
Author(s):  
Madhuchhanda Kundu ◽  
Sumita Raha ◽  
Avik Roy ◽  
Kalipada Pahan
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Healthy Controls ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Patient Derived Xenograft

Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p402) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p402. The level of p40 was also larger than p402 in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4+IFNγ+ and CD8+IFNγ+ T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor β (TGFβ) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.

Clinicopathologic characteristics of triple-negative breast cancer and relationship to basal markers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11519-e11519
Author(s):  
Dimitrios Tryfonopoulos ◽  
Georgios Oikonomopoulos ◽  
Stamatina Demiri ◽  
Lazaros Lekakis ◽  
Nikolaos Fragkiskos Pistamaltzian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Stage Iv ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Clinicopathologic Characteristics ◽  
Ki 67 ◽  
Immunohistochemical Markers ◽  
Gene Expression Studies

e11519 Background: Triple negative breast cancers are immunohistochemical surrogates of basal-like breast cancers. There is no complete overlap between triple negative and basal-like tumors and as gene expression studies evolve, further subclassification bearing clinical relevance is underway. Our purpose was to correlate clinicopathologic characteristics of triple negative breast cancer tumors with expression of basal markers in an effort to define immunohistochemically subgroups of this heterogenous disease Methods: Data were retrieved and analysed using our electronic databank. Patient samples were reviewed by an expert breast cancer pathologist and stained additionally for EGFR and CK 5/6 antibodies. Results: Sixty-five women with triple negative breast cancer were identified. Mean age was 58.3±12.9 years. Most tumors (86%) were of ductal histology, 53% grade 3, 48% having high Ki-67 index (>14%). 10% of patients presented with Stage IV, 25% with Stage III, 38% with stage II and 27% with stage I disease. 63% of patients were postmenopausal. EGFR staining was present in 43% of tumor samples, whereas CK 5/6 in 38.5%. Both EGFR and CK 5/6 expression was found in 18.5%, whereas 37% of tumors expressed neither EGFR or CK 5/6. No difference was observed between tumors expressing any of these 2 basal markers as compared to EGFR and CK 5/6 negative tumors in terms of Ki-67 index, grade, tumor size and nodal involvement. Lymphovascular invasion and non-ductal histology tended to occur more frequently (p=ns) in non-basal tumors. Additionally, patients with expression of any of the basal markers tended to be more obese than the non-basal triple negative breast cancer patients (p=ns). Conclusions: Further immunohistochemical markers apart from EGFR and CK 5/6 are needed in order to further define clinically meaningful subgroups of triple negative breast cancer.

scholarly journals Androgen Receptor Expression in Triple-Negative Breast Cancer

2019 ◽  
pp. 90-94
Author(s):  
Samane Jam ◽  
Alireza Abdollahi ◽  
Sanaz Zand ◽  
Zahra Khazaeipour ◽  
Ramesh Omranipour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Lymphovascular Invasion ◽  
Triple Negative ◽  
Tumor Grade ◽  
Receptor Expression ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cross Sectional

Background: Triple-negative breast cancer (TNBC) accounts for 15 to 20% of all breast cancers. These patients do not benefit from hormone therapy and other targeted treatments of breast cancer. Recently, researchers proposed the use of androgen receptor (AR)-targeted therapies in this subset of patients. The rate of AR expression in TNBC patients varies from 0 to 53%. AR positivity is associated with a better outcome for breast cancer patients. The purpose of this study was to evaluate AR status in TNBC patients and its association with other demographic and pathologic features.Methods: This cross-sectional study was conducted in the Cancer Institute of Iran, affiliated with Tehran University of Medical Sciences, in 2015. Archived formalin-fixed, paraffin-embedded breast tumor blocks were evaluated to determine the AR status of the tumors. Demographic and pathologic characteristics of the patients were retrieved from the department of pathology database. Data were analyzed with SPSS 18.0.Results: Seventy-seven TNBC patients with the mean age of 45.3 ± 11.5 were assessed. Twenty-six patients (34%) showed AR expression, and 51 patients (56%) did not have AR expression. There was no significant correlation between AR status and age, tumor size, histopathologic type of tumor, or lymph node involvement. However, AR positivity had a statistically significant association with a lower tumor grade and lymphovascular invasion (P = 0.029 and P = 0.01, respectively).Conclusion: TNBC patients with AR expression tend to have lower tumor grades and higher rates of lymphovascular invasion.

scholarly journals Disease-free Probability and Triple-Negative Breast Cancer

2012 ◽  
Vol 35 (1) ◽  
pp. 5-13
Author(s):  
Prakasit Chirappapha ◽  
Thongchai Sukarayothin ◽  
Yodying Wasuthit ◽  
Ronnarat Suvikapalornkul ◽  
Panuwat Lertsithichai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Local Recurrence ◽  
Triple Negative Breast Cancer ◽  
Distant Metastasis ◽  
Triple Negative ◽  
Free Probability ◽  
Growth Factor Receptor ◽  
Tumor Stage ◽  
Breast Cancers ◽  
Breast Cancer Patients

Objective: To compare the probabilities of local recurrence and distant metastasis between women with triple-negative and non- triple negative breast cancers. Methods: Medical and pathological records of breast cancer patients treated between the years 2002 and 2006 were reviewed. Results: There were 256 patients with complete data on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) expression determinations. There were 54 patients (21%) with triple-negative (ER-, PR-, HER2 -) cancers. Triple-negative patients were more likely to have larger tumors with higher histologic grade. The median fallow-up time was 4 years. The probabilities of local and distant recurrence were similar between the two groups of patients. Only two factors were independently and significantly associated with overall recurrence: tumor stage and tumor size. Conclusion: Triple-negative breast cancer did not have a higher risk for both local recurrence and distant metastasis when compared with non-triple negative cancer.

Comparison of serum levels of CEA and CA 15–3 in triple-negative breast cancer at the time of metastases and serum levels at the time of first diagnosis

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e12017-e12017
Author(s):  
D. Sener Dede ◽  
S. Aksoy ◽  
N. Bulut ◽  
O. Dizdar ◽  
Z. Arik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Serum Levels ◽  
Breast Cancers ◽  
Negative Group ◽  
Breast Cancer Patients ◽  
Serum Cea

e12017 Background: Cancer antigen 15–3 (CA 15–3) and carcinoembryonic antigen (CEA), are often used in follow up care of breast cancer and provide important clues to the clinicians for disease progression in metastatic and recurrent breast cancer. Triple-negative breast cancers are frequently defined as a single group identifiable using routine clinical tests. They are negative for estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), the so-called triple-negative breast cancers. In this study we compared the tumor markers of triple negative breast cancer and non-triple negative patients. Methods: We retrospectively analyzed serum CEA and CA 15–3 levels of both triple negative and non-triple negative breast cancer patients at the time of first diagnosis and when they developed metastatic disease. Results: 544 consecutive nonmetastatic breast cancer patients presenting at Hacettepe University Institute of Oncology, Ankara, Turkey, with a median age of 49 were evaluated. 15.1% of the patients were triple negative breast cancer. At the time of diagnosis triple negative group had lower serum CEA (2.5 ± 5.9 vs 4.0 ±16.4 p = 0.35) and CA 15–3 (23.7 ± 14.6 vs 37.1 ± 117; p = 0.021) levels compared to non-triple negative group. In patients who developed metastasis during follow up; the CEA (3.2 ± 3.8 vs 29.6 ± 106.4 p = 0.022) and CA15–3 (46.9 ± 46.3 vs 203.2 ± 534 p = 0.008) levels were also significantly lower in triple negative breast cancer group compared to non-triple negative group.In non-triple negative breast cancer patients who developed metastasis, mean serum levels of CEA and CA15–3 significantly increased compared to baseline, whereas in triple negative group who developed metastasis CEA and CA 15–3 levels did not differ significantly. Conclusions: While being a good laboratory parameter in the follow-up of patients with breast cancer metastases, tumor markers may not show the increased tumor burden in the triple-negative breast cancer patients. No significant financial relationships to disclose.

Clinical characteristics and chemotherapy options of triple-negative breast cancer: Role of classical CMF regimen.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1053-1053
Author(s):  
Min Hee Hur ◽  
Tae Ho Kang ◽  
Ra Joo Im ◽  
Se Won Kim ◽  
Chan Seok Yoon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Positive Lymph Node ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Clinicopathologic Characteristics ◽  
Large Tumor ◽  
Survival Difference ◽  
High Stage

1053 Background: Triple-negative breast cancer is a high risk breast cancer that lacks the benefit of specific targeted therapy. We investigated the clinicopathologic characteristics between triple-negative breast cancers (TNBC) and non-TNBC. And we also analyzed the effect of chemotherapy options such as classical CMF regimen, anthracycline-based, or taxane-based chemotherapy. Methods: A total of 826 invasive breast cancer patients were evaluated from March 2003 to December 2008. We investigated them retrospectively, who had the median follow-up for 88 months. We examined the differences between TNBC compared with non-TNBC in relation to the clinicopathologic parameters, chemotherapy regimen, overall survival (OS). Results: 156 (18.9%) cases among 826 patients were triple negative breast cancers. There were significantly positive associations with younger age (below 35 years), large tumor (>2cm), high stage, poorly differentiated nuclear grade, poorly histologic grade in TNBC. Positive lymph node, lymphovascular invasion were not significantly different between TNBC and non- TNBC. A total of 677 patients were treated with chemotherapy. In TNBC patients, 142 (93.4%) patients were treated with chemotherapy more than in 535 (61.4%) of non- TNBC patients. The chemotherapy in TNBC patients was composed of classical CMF (47.9%), anthracycline-based regimen (25.4%), taxane-based regimen (26.8%). 19 cases (12%) of TNBC experienced locoregional or systemic metastases. 48 (7.2%) patients of non- TNBC did local or systemic metastases. Patients with TNBC had worse 5-year OS than with non-TNT (95.7% vs 98.6%, p=0.01). Interestingly, patients treated with CMF regimen were better 5-year OS than with anthracycline-based, or taxane-based regimen in TNBC (100% vs 96.9% vs 89.2%, p=0.001). There was no survival difference among chemotherapy regimens in non-TNBC patients. Conclusions: Patients with TNBC have poor prognosis compared with non-TNBC. Classical CMF regimen for TNBC patients may be more effective than anthracycline-based or taxane-based regimens.

Prevalence of androgen receptors expression in triple negative breast cancer patients and its correlation with clinicopathological criteria: Our institutes experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12584-e12584 ◽  
Author(s):  
Kamel Farag ◽  
Ola Elfarargy ◽  
Shereen El Shorbagy ◽  
Safa Ahmed ◽  
Ola Harb ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Androgen Receptors ◽  
Distant Metastases ◽  
Clinicopathological Parameters ◽  
P Value ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Positive Expression

e12584 Background: Triple negative breast cancer (TNBC) is a term that has been applied to breast cancers which lack expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). It represents about 20% of breast cancers diagnosed worldwide. TNBC is a challenging type by its presentation criteria and limited options of treatment. Continuous research for finding specific target is the aim of scientists. Androgen receptors (AR) expression take special attention in this type of breast cancer as its expression can help for finding special targeted treatment as antiandrogen therapy.Purpose:is to assess the AR expression in TNBC patients and to correlate its expression with clinicopathological parameters and disease outcome of patients in study populations. Methods: This prospective study included 90 female patients confirmed as TNBC patients in medical oncology and clinical oncology departments, in Mansoura University and Zagazig University, Egypt, between December, 2013 to May, 2016. AR positive expression was defined as ≥10% nuclear immunostaining. Results: AR expression was positive in twenty seven (27/90) patients (30% ), and lack of its expression was significantly associated with younger age group(p < 0.001), higher grade(p = 0.017)& higher tumor stage(p < 0.001), presence of lymph node metastasis(p < 0.001) & distant metastases(p = 0.032), vascular(p = 0.044)& perineural invasion and high baseline CA 15-3 level (p < 0.001).Median follow up duration was 17.5months (range 6-40), 32/90 died (35.6%).Mean OS was 28months for AR negative TNBC patients versus 32months for AR positive patients. Twenty four of died patients (24/32) were AR negative. Three years OS was 50.8% and 44.1% for AR positive and AR negative respectively, but with nonsignificant P-value. Conclusions: Our study confirmed that AR positive expression in TNBC is a good prognostic feature and it can be sued as target for antiandrogen therapy in this group who is lacking any targettreatment.

scholarly journals METTL14 and miR-1247 are associated with poor outcomes in Triple-Negative Breast Cancer

2020 ◽  
Author(s):  
Junbo Hu ◽  
Mingyue Hou ◽  
Bo Chen ◽  
Huan Wu ◽  
You Cai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Diagnostic Tools ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cox Regression Analysis ◽  
Expression Levels ◽  
Poor Outcomes

Abstract BackgroundTriple-negative breast cancer (TNBC) doesn’t have targets for therapy, and accounts for 15% of all breast cancers. m6A modification has been reported to play important role in the progression of various cancers. However, the expression and function of the m6A methyltransferase METTL14 in TNBC are unclear. MethodsThe count data of miRNA and mRNA of breast cancer patients with both tumor tissues and matched nomal tissues were downloaded from the TCGA data portal. The expression of METTL14 was determined by immunohistochemistry and western blot. The expression of has-miR-1247 was determined by qRT-PCR.The Cox regression analysis was executed for the expression levels of METTL14 and DEmiRNAs .The Kaplan-Meier survival analysis were performed to establish the correlation between the expression level and survival of BC patients .ResultsWe discovered that METTL14 was significantly downregulated in TNBC tissues, and low expression of METTL14 is correlated with worse differentiation ,higher ki67 proliferation and poorer survival suggesting its potential as an independent prognostic biomarker for TNBC. We also found the positive correlation between the expression levels of METTL14 and has-miR-1247. Moreover, has-miR-1247 was significantly downregulated in TNBC tissues, and lead to poorer survival.ConclusionOur data suggested that METTL14 and miR-1247 could be valuable diagnostic tools, prognostic biomarkers, and therapeutic targets for TNBC.

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