scholarly journals Obesity Modulates the Gut Microbiome in Triple-Negative Breast Cancer

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3656
Author(s):  
Fokhrul Hossain ◽  
Samarpan Majumder ◽  
Justin David ◽  
Bruce A. Bunnell ◽  
Lucio Miele
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Gut Microbiome ◽  
Triple Negative ◽  
Alpha Diversity ◽  
Low Grade ◽  
Syngeneic Mouse Model ◽  
Variation Of Functional ◽  
Analysis Of Variation ◽  
The Impact

Triple-negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer. Obesity is associated with increased incidence and worse prognosis in TNBC through various potential mechanisms. Recent evidence suggests that the gut microbiome plays a central role in the progression of cancer, and that imbalances or dysbiosis in the population of commensal microbiota can lead to inflammation and contribute to tumor progression. Obesity is characterized by low-grade inflammation, and gut dysbiosis is associated with obesity, chronic inflammation, and failure of cancer immunotherapy. However, the debate on what constitutes a “healthy” gut microbiome is ongoing, and the connection among the gut microbiome, obesity, and TNBC has not yet been addressed. This study aims to characterize the role of obesity in modulating the gut microbiome in a syngeneic mouse model of TNBC. 16S rRNA sequencing and metagenomic analyses were performed to analyze and annotate genus and taxonomic profiles. Our results suggest that obesity decreases alpha diversity in the gut microbiome. Metagenomic analysis revealed that obesity was the only significant factor explaining the similarity of the bacterial communities according to their taxonomic profiles. In contrast to the analysis of taxonomic profiles, the analysis of variation of functional profiles suggested that obesity status, tumor presence, and the obesity–tumor interaction were significant in explaining the variation of profiles, with obesity having the strongest correlation. The presence of tumor modified the profiles to a greater extent in obese than in lean animals. Further research is warranted to understand the impact of the gut microbiome on TNBC progression and immunotherapy.

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 EGCG Inhibits Adipose-Derived Mesenchymal Stem Cells Differentiation into Adipocytes and Prevents a STAT3-Mediated Paracrine Oncogenic Control of Triple-Negative Breast Cancer Cell Invasive Phenotype

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1506
Author(s):  
Narjara Gonzalez Suarez ◽  
Sahily Rodriguez Torres ◽  
Amira Ouanouki ◽  
Layal El Cheikh-Hussein ◽  
Borhane Annabi
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cell Differentiation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Stem Cell Differentiation ◽  
Low Grade ◽  
Invasive Phenotype ◽  
Fatty Acid Binding

Obese subjects have an increased risk of developing triple-negative breast cancer (TNBC), in part associated with the chronic low-grade inflammation state. On the other hand, epidemiological data indicates that increased consumption of polyphenol-rich fruits and vegetables plays a key role in reducing incidence of some cancer types. Here, we tested whether green tea-derived epigallocatechin-3-gallate (EGCG) could alter adipose-derived mesenchymal stem cell differentiation into adipocytes, and how this impacts the secretome profile and paracrine regulation of the TNBC invasive phenotype. Here, cell differentiation was performed and conditioned media (CM) from preadipocytes and mature adipocytes harvested. Human TNBC-derived MDA-MB-231 real-time cell migration was performed using the exCELLigence system. Differential gene arrays and RT-qPCR were used to assess gene expression levels. Western blotting was used to assess protein expression and phosphorylation status levels. In vitro vasculogenic mimicry (VM) was assessed with Matrigel. EGCG was found to inhibit the induction of key adipogenic biomarkers, including lipoprotein lipase, adiponectin, leptin, fatty acid synthase, and fatty acid binding protein 4. Increased TNBC-derived MDA-MB-231 cell chemotaxis and vasculogenic mimicry were observed in response to mature adipocytes secretome, and this was correlated with increased STAT3 phosphorylation status. This invasive phenotype was prevented by EGCG, the JAK/STAT inhibitors Tofacitinib and AG490, as well as upon STAT3 gene silencing. In conclusion, dietary catechin-mediated interventions could, in part through the inhibition of adipogenesis and modulation of adipocytes secretome profile, prevent the onset of an obesogenic environment that favors TNBC development.

scholarly journals Antiangiogenic therapy for breast cancer with triple negative phenotype

2021 ◽  
Vol 23 (1) ◽  
pp. 88-92
Author(s):  
Inna P. Ganshina ◽  
Kristina A. Ivanova ◽  
Olga O. Gordeeva ◽  
Aleksandr V. Arkhipov ◽  
Liudmila G. Zhukova
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Malignant Tumors ◽  
Antiangiogenic Therapy ◽  
Treatment Strategies ◽  
Her 2 ◽  
Triple Negative Phenotype ◽  
The Impact ◽  
Negative Phenotype

Triple-negative breast cancer is 1024% of all cases of breast cancer and is characterized by the absence of estrogen, progesterone, and HER-2 receptors in the tumor. The therapy of this illness is a difficult clinical case. In contrast to hormone-positive and HER-2-positive phenotypes, in which we successfully use targeted drugs (antiestrogens and anti-HER-2 drugs), for triple-negative breast cancer we have not had such targets for a long time. Thus, despite the impressive results of immunotherapy of triple-negative breast cancer, there remains a fairly large group of patients with negative PD-L1 status, for whom it is necessary to develop other treatment strategies. One of the approaches in the treatment of malignant tumors includes not the impact on tumor cells, but the process of angiogenesis. Antiangiogenic drugs have positively proven themselves in the treatment of a large number of malignant tumors but are underestimated for breast cancer (including triple-negative phenotype). The use of bevacizumab in combinations with cytostatic drugs in breast cancer therapy (including triple-negative breast cancer) has been studied in a large number of clinical trials but was undeservedly forgotten in some countries due to the revoked FDA registration. This review presents the role of bevacizumab in the treatment of patients with triple-negative breast cancer and suggests the conditions when the administration of this drug is justified and leads to better results.

scholarly journals Muscadine Grape Extract Reduces Lung and Liver Metastasis in Mice with Triple Negative Breast Cancer in Association with Changes in the Gut Microbiome (P05-017-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Marianne Collard ◽  
Nataleigh Austin ◽  
Ann Tallant ◽  
Patricia Gallagher
Keyword(s):  
Breast Cancer ◽  
Fatty Acids ◽  
Gut Microbiota ◽  
Triple Negative Breast Cancer ◽  
Gut Microbiome ◽  
Triple Negative ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Muscadine Grape ◽  
Chain Fatty Acids

Abstract Objectives The goal of this study was to determine if a proprietary muscadine grape seed and skin extract (MGE) inhibits triple negative breast cancer (TNBC) metastasis and alters the gut microbiota. Methods 4T1 TNBC cells were injected into the mammary fat pad of 6-week-old female Balb/c mice. After 2 weeks, tumors were surgically removed and mice were placed into a control group (n = 8) or a treatment group that received 0.1 mg/mL total phenolics MGE (Piedmont R&D) in the drinking water (n = 8). Mice were sacrificed after 4 weeks; tissues and fecal samples were collected for analysis. Immunohistochemistry (Ki67, α-SMA) and hemotoxylin and eosin staining were used to quantify metastases using the inForm© 2.2 software. Gut microbial composition was determined by 16S rRNA sequencing and short chain fatty acids were detected by gas chromatography (Microbiome Insights). Data are expressed as means ± SEM using student's t-test. Results MGE reduced Ki67 cell positivity in the lungs and livers of mice, indicating reduced metastatic proliferation (9.3 ± 0.9% vs 6.2 ± 0.7% and 5.0 ± 1.5% vs 0.77 ± 0.2% cells, respectively; P < 0.01), and decreased cancer associated fibroblasts in the lungs (5.3 ± 1.0% vs 3.0 ± 0.5% cells; P < 0.05), which are associated with metastasis. MGE significantly reduced the number (4.7 ± 0.7 vs 2.2 ± 0.4 tumors/field; P < 0.01) and size (1358 ± 48 vs 1121 ± 47 pixels; P < 0.01) of liver metastases, resulting in decreased metastatic tumor burden (6656 ± 1220 vs 3096 ± 644 total area in pixels; P < 0.01). Attenuated TNBC metastasis correlated with MGE-induced changes in gut microbiota. Alpha diversity (4.15 ± 0.10 vs 4.51 ± 0.13 Shannon index; P < 0.05) and the Firmicutes to Bacteroidetes ratio (0.37 ± 0.07 vs 0.76 ± 0.12; P < 0.05) were significantly increased in MGE-treated mice, indicating enhanced microbial richness and increased energy harvest by the gut microbiome. Butyrate-producing bacteria, such as Ruminococcus, Butyricicoccus and Lachnospiraceae, were increased with MGE (P < 0.05) as well as the anti-inflammatory compound butyrate relative to other short-chain fatty acids (25.0 ± 2.7% vs 75.3 ± 15.5%; P < 0.01). Conclusions These data show that MGE attenuates TNBC metastasis in association with alterations in the gut microbiome, suggesting that MGE may be an effective treatment against TNBC metastatic progression. Funding Sources Chronic Disease Research Fund.

The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics

2016 ◽  
pp. 34-42 ◽  
Author(s):  
Carey K. Anders ◽  
Vandana Abramson ◽  
Tira Tan ◽  
Rebecca Dent
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Pathologic Complete Response ◽  
Future Research ◽  
Research Strategies ◽  
Molecular Features ◽  
Platinum Salts ◽  
The Impact

Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as “immune-activated,” consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.

scholarly journals Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

2015 ◽  
Vol 33 (1) ◽  
pp. 13-21 ◽  
Author(s):  
William M. Sikov ◽  
Donald A. Berry ◽  
Charles M. Perou ◽  
Baljit Singh ◽  
Constance T. Cirrincione ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Stage Ii ◽  
Open Label ◽  
Grade 3 ◽  
Dose Dense ◽  
The Impact

Purpose One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. Patients and Methods Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m2 once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. Results Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. Conclusion In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.

Triple-negative breast cancer: the impact of guideline-adherent adjuvant treatment on survival—a retrospective multi-centre cohort study

2011 ◽  
Vol 132 (3) ◽  
pp. 1073-1080 ◽  
Author(s):  
L. Schwentner ◽  
R. Wolters ◽  
K. Koretz ◽  
M. B. Wischnewsky ◽  
R. Kreienberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cohort Study ◽  
Triple Negative Breast Cancer ◽  
Adjuvant Treatment ◽  
Triple Negative ◽  
The Impact

scholarly journals Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Milica Nedeljković ◽  
Nikola Tanić ◽  
Tatjana Dramićanin ◽  
Zorka Milovanović ◽  
Snežana Šušnjar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Marker ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Clinical Course ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
The Impact

Summary Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

scholarly journals 3-Bromopyruvate-mediated MCT1-dependent metabolic perturbation sensitizes triple negative breast cancer cells to ionizing radiation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Irini Skaripa-Koukelli ◽  
David Hauton ◽  
John Walsby-Tickle ◽  
Eloïse Thomas ◽  
Joshua Owen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Redox Homeostasis ◽  
Nucleotide Synthesis ◽  
Monocarboxylate Transporter 1 ◽  
Metabolic Perturbation ◽  
The Impact

Abstract Background Triple negative breast cancer (TNBC) poses a serious clinical challenge as it is an aggressive form of the disease that lacks estrogen receptor, progesterone receptor, and ERBB2 (formerly HER2) gene amplification, which limits the treatment options. The Warburg phenotype of upregulated glycolysis in the presence of oxygen has been shown to be prevalent in TNBC. Elevated glycolysis satisfies the energy requirements of cancer cells, contributes to resistance to treatment by maintaining redox homeostasis and generating nucleotide precursors required for cell proliferation and DNA repair. Expression of the monocarboxylate transporter 1 (MCT1), which is responsible for the bidirectional transport of lactate, correlates with an aggressive phenotype and poor outcome in several cancer types, including breast cancer. In this study, 3-bromopyruvate (3BP), a lactate/pyruvate analog, was used to selectively target TNBC cells that express MCT1. Methods The cytotoxicity of 3BP was tested in MTT assays using human TNBC cell lines: BT20 (MCT1+/MCT4−), MDA-MB-23 (MCT1−/MCT4+), and BT20 in which MCT1 was knocked down (siMCT1-BT20). The metabolite profile of 3BP-treated and 3BP-untreated cells was investigated using LC-MS/MS. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of BT20 and MDA-MB-231 cells treated with 3BP were measured using a Seahorse XF96 extracellular flux analyzer. The impact of ionizing radiation on cell survival, alone or in combination with 3BP pre-treatment, was evaluated using clonogenic assays. Results Metabolomic analyses showed that 3BP causes inhibition of glycolysis, disturbance of redox homeostasis, decreased nucleotide synthesis, and was accompanied by a reduction in medium acidification. In addition, 3BP potentiated the cytotoxic effect of ionizing radiation, a treatment that is frequently used in the management of TNBC. Conclusions Overall, MCT1-mediated metabolic perturbation in combination with radiotherapy is shown to be a promising strategy for the treatment of glycolytic tumors such as TNBC, overcoming the selectivity challenges of targeting glycolysis with glucose analogs.

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