Gut Metabolites and Breast Cancer: The Continuum of Dysbiosis, Breast Cancer Risk, and Potential Breast Cancer Therapy
Abstract
:1. Introduction
1.1. The Gut Microbiota and Its Metabolites
1.2. The Crosstalk between Gut Metabolites and the Host Immune System
2. Methods
2.1. Search Strategy
2.2. Data Extraction
3. Results
Metabolite Group | Metabolite | Cancer Type | Type of Study | Cancer Cell Line/Animal Type | Type of Assay | Inhibitory Effect | Reference |
---|---|---|---|---|---|---|---|
Bacteriocin | Nisin | Breast | In vitro | MCF7 | 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) | High cytotoxicity with the IC50 value of 5 μM, and selectivity against the MCF7 cells. | [16] |
Nisin | Breast | In vitro | MCF7 | MTT | Decreased cell viability in a concentration-dependent manner with the IC50 value of 105.46 μM. | [17] | |
Short-chain fatty acids | Sodium Butyrate | Breast | In vitro | MCF7 | MTT | Inhibited cell proliferation in a dose-dependent manner with the IC50 value of 1.26 mM. Induced morphological changes to the MCF7 cells, and cell cycle arrest in the G1 phase. | [18] |
Sodium Butyrate | Breast | In vitro | MCF7 | Cell counting kit-8 (CCK-8) and Western blot | Inhibited MCF7 cell viability in a dose- and time-dependent manner, decreased B-cell lymphoma 2 (Bcl-2) protein expression, and induced morphological changes. | [19] | |
Sodium Butyrate | Breast | In vitro | MCF7 and MB-MDA-468 | MTT and Annexin-V-FITC | Induced cytotoxicity and apoptosis in both breast cancer cell lines, and increased expression of 15-lipoxygenase type 1 (15-Lox-1) and production of 13-Hydroxyoctadecadienoic acid (13(S)HODE). | [20] | |
Sodium Butyrate | Breast | In vitro | MCF7, T47-D, and MDA-MB-231 | MTT and sulforhodamine B (SRB) | Initiated epigenetic changes to acetylation of proteins; pyruvate kinase activity was increased in MDA-MB-231 cells and lactate dehydrogenase activity was increased in T47-D cells. Increased oxygen consumption in the MDA-MB-231 and T47-D cell lines. | [21] | |
Sodium Butyrate | Breast | In vitro | MCF7 | CCK-8 | Inhibited cell proliferation in a dose- and time-dependent manner. Induced cell cycle arrest in the G1/G2 phase and a decrease in the S phase and caused chromatin relaxation. | [22] | |
Butyrate | Breast | In vitro | MCF7 | Western blot and polymerase chain reaction (PCR) | Cell inhibition of 34% against MCF7 cells, increased histone H3K9 acetylation, and increased expression of p21waf1 and Retinoic acid receptor beta (RARβ). | [23] | |
Sodium Butyrate | Breast | In vitro | SKBR3 | MTT | Combined treatment of NaB and trastuzumab demonstrated synergistic growth inhibition and elevated mRNA and protein levels of p27Kip1. | [24] | |
Sodium Butyrate | Breast | In vitro | MRK-nu-1 | Western blot and caspase assay | Induction of caspase-3, -10, and -8, and formation of DNA fragmentation, in a dose- and time-dependent manner. Triggered apoptosis via the induction of caspase-10 activity. | [25] | |
Sodium Butyrate | Breast | In vitro | MCF7 | MTT | Inhibited cell growth of MCF7 cells dose-dependently, induced cell cycle arrest in the G2/M phase, reduced p53 expression, decreased Bcl-2 mRNA and protein levels, increased apoptosis, and reduced glutathione levels. | [26] | |
Sodium Butyrate | Breast | In vitro | MCF7 | Western blot and flow cytometry | Induced cell cycle arrest and apoptosis via interaction with p21waf1/cip1 with cyclin-dependent kinase (CDK) and decreased proliferating cell nuclear antigen (PCNA) levels. | [27] | |
Sodium Butyrate | Breast | In vitro | MCF7, T47-D, and BT-20 | Western blot | Increased the expression of tumour necrosis factor receptor 1 (TNF-R1) and receptor 2 (-R2), TRAIL receptor 1 (TRAIL-R1) and receptor 2 (-R2), and Fas in MCF7 cells and acted synergistically with these receptors to inhibit cell proliferation and induced apoptosis via p21waf1 and its interaction with PCNA. | [28] | |
Sodium Butyrate | Breast | In vitro | MCF7, MCF-7ras, T47-D, BT-20, and MDA-MB-231 | Western blot and PCR | Inhibited cell proliferation in all cell lines. Induced cell cycle arrest in the G2/M phase in MDA-MB-231 cells, and in the G1 phase for the other four cell lines. Inhibited cell growth in a p53-independent manner and induced apoptosis via the Fas/Fas L system. | [29] | |
Sodium Butyrate | Breast | In vitro | MCF7 | MTT | Increased bioavailability when coupled with the hyaluronic acid drug delivery system due to the ability to bind to CD44 receptors, which are prominent on tumour surfaces. | [30] | |
Sodium Butyrate | Breast | In vitro | MDA-MB-231 | Flow cytometry, Western blot, and protein array analysis | Induced cell cycle arrest in the G2 phase via the inhibition of histone H1 kinase activities, and increased levels of p21waf1. | [31] | |
Sodium Butyrate | Breast | In vitro | MCF7, MDA-MB-231, T47-D, and BT-20 | Flow cytometry and Burton method to assess variation of DNA content | Inhibitory effect of 85-90% with a dose- and time-dependent inhibition of cell proliferation, induced cell cycle arrest in the G2/M phase, resulting in the induction of apoptosis in the estrogen receptor-positive cell lines MCF7 and T47-D. | [32] | |
Sodium Butyrate | Breast | In vitro | MCF7 | Estrogen receptor assays | Initiated significant hyperacetylation of histones in MCF7 cells and lowered estrogen receptor levels. | [33] | |
Sodium Butyrate | Breast | In vitro | MCF7 | CEA-Roche and Biorad protein assay | Induced morphological changes in MCF7 cells and reduced cell proliferation. | [34] | |
Natural purine nucleoside | Inosine | Breast | In vitro | MCF7 and MDA-MB-231 | CyQuant XTT | Demonstrated primary cytoprotective activities during breast cancer hypoxia, rather than adenosine, which was previously thought to be the primary compound responsible for this bioactivity. | [35] |
Metabolite Group | Metabolite | Cancer Type | Clinical Study Details | Clinical Observations | Reference |
---|---|---|---|---|---|
Short-chain fatty acids | Butyric acids, propionate, and acetate | Colorectal | A case-control study with 14 colorectal cancer (CRC) patients and 14 non-CRC subjects. | A decreasing abundance of SCFA-producing bacterium, e.g., Bifidobacterium, in CRC patients in comparison to non-CRC participants. The levels of all three SCFAs assessed were reduced in CRC patients, and the values for butyric acid and propionate were statistically significant. | [36] |
Acetic, propionic, butyric, valeric, and plasma isovaleric acid | Solid cancer tumours | Prospective cohort biomarker study of 52 patients with solid cancer tumours that completed programmed cell death-1 inhibitors (PD-1i) therapy. | High concentrations of all SCFAs correlated with extended progression-free survival, and it was indicated that SCFA concentrations in stool samples may be associated with PD-1i efficacy. | [37] | |
Butyrate and propionate | Breast | Conducted 16S rRNA gene sequencing, cell culture methods, and targeted metabolomics on faecal samples from premenopausal breast cancer patients and premenopausal healthy participants. | The abundance of SCFA-producing bacteria and enzymes was significantly reduced in premenopausal breast cancer patients in comparison to premenopausal healthy participants, and the overall composition of the gut microbiota differed substantially between the two groups. | [38] | |
Bacteriocin | Azurin-p28 peptide | P53(+) metastatic solid tumours | NSC745104: Phase I human clinical trial of azurin-p28 in 15 patients (aged 47–80 years old) with p53(+) metastatic solid tumours | Participants did not exhibit an immune response to p28, significant adverse events, or dose-limiting toxicities. Indicative of a highly favourable therapeutic index for anticancer activity. | [39] |
Azurin-p28 peptide | Central nervous system (CNS) tumours | NSC745104: Phase I human clinical trial on 18 children aged 3–21 years old with progressive or recurrent CNS tumours | The p28 peptide was well-tolerated in children with CNS tumours at the recommended adult phase II dose (4.16 mg/kg/dose), which correlated closely with the previous study on adult participants. The primary adverse event was grade 1 infusion-related reactions; however, these often did not require treatment and were short-lived. | [40] |
4. The Correlation between Gut Metabolites and Breast Cancer Development
4.1. The Microbiota of Healthy Breast Versus Breast Tumour Microenvironment
4.2. Microbial Dysbiosis and Breast Cancer Growth
5. Anticancer Action of Nisin against Breast Cancer
6. The Duality of Sodium Butyrate in Breast Cancer
The Anticancer Action of Butyrate against BC
7. Potential Implementation of Inosine in Breast Cancer Therapy
8. Gut Microbial Metabolites and Clinical Research in Breast Cancer
8.1. Clinical Studies Exploring the Association between Gut Metabolites and Cancer Development
8.2. Gut Metabolites and Standard Chemotherapies
9. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
References
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Jaye, K.; Chang, D.; Li, C.G.; Bhuyan, D.J. Gut Metabolites and Breast Cancer: The Continuum of Dysbiosis, Breast Cancer Risk, and Potential Breast Cancer Therapy. Int. J. Mol. Sci. 2022, 23, 9490. https://doi.org/10.3390/ijms23169490
Jaye K, Chang D, Li CG, Bhuyan DJ. Gut Metabolites and Breast Cancer: The Continuum of Dysbiosis, Breast Cancer Risk, and Potential Breast Cancer Therapy. International Journal of Molecular Sciences. 2022; 23(16):9490. https://doi.org/10.3390/ijms23169490
Chicago/Turabian StyleJaye, Kayla, Dennis Chang, Chun Guang Li, and Deep Jyoti Bhuyan. 2022. "Gut Metabolites and Breast Cancer: The Continuum of Dysbiosis, Breast Cancer Risk, and Potential Breast Cancer Therapy" International Journal of Molecular Sciences 23, no. 16: 9490. https://doi.org/10.3390/ijms23169490