Metabolomics-Microbiome Crosstalk in the Breast Cancer Microenvironment

Breast cancer, the most frequent cancer diagnosed among females, is associated with a high mortality rate worldwide. Alterations in the microbiota have been linked with breast cancer development, suggesting the possibility of discovering disease biomarkers. Metabolomics has emerged as an advanced promising analytical approach for profiling metabolic features associated with breast cancer subtypes, disease progression, and response to treatment. The microenvironment compromises non-cancerous cells such as fibroblasts and influences cancer progression with apparent phenotypes. This review discusses the role of metabolomics in studying metabolic dysregulation in breast cancer caused by the effect of the tumor microenvironment on multiple cells such as immune cells, fibroblasts, adipocytes, etc. Breast tumor cells have a unique metabolic profile through the elevation of glycolysis and the tricarboxylic acid cycle metabolism. This metabolic profile is highly sensitive to microbiota activity in the breast tissue microenvironment. Metabolomics shows great potential as a tool for monitoring metabolic dysregulation in tissue and associating the findings with microbiome expression.

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Molecular Profiles of Matched Primary and Metastatic Tumor Samples Support a Linear Evolutionary Model of Breast Cancer

10.1101/667303 ◽

2019 ◽

Author(s):

Runpu Chen ◽

Steve Goodison ◽

Yijun Sun

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Evolutionary Model ◽

Metastatic Tumor ◽

Cancer Diagnostics ◽

Tumor Evolution ◽

Paired Data ◽

Cancer Subtypes ◽

Cancer Data ◽

Progression Model

AbstractThe interpretation of accumulating genomic data with respect to tumor evolution and cancer progression requires integrated models. We developed a computational approach that enables the construction of disease progression models using static sample data. Application to breast cancer data revealed a linear, branching evolutionary model with two distinct trajectories for malignant progression. Here, we used the progression model as a foundation to investigate the relationships between matched primary and metastasis breast tumor samples. Mapping paired data onto the model confirmed that molecular breast cancer subtypes can shift during progression, and supported directional tumor evolution through luminal subtypes to increasingly malignant states. Cancer progression modeling through the analysis of available static samples represents a promising breakthrough. Further refinement of a roadmap of breast cancer progression will facilitate the development of improved cancer diagnostics, prognostics and targeted therapeutics.

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Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression

Cells ◽

10.3390/cells10102641 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2641

Author(s):

Chun-Chao Wang

Keyword(s):

Breast Cancer ◽

Mammary Gland ◽

Cancer Progression ◽

Cancer Metabolism ◽

Experimental Models ◽

Premalignant Lesions ◽

Primary Tumors ◽

Cancer Subtypes ◽

Mammary Gland Morphogenesis ◽

Gland Morphogenesis

Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.

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Engineering Breast Cancer On-chip—Moving Toward Subtype Specific Models

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.694218 ◽

2021 ◽

Vol 9 ◽

Author(s):

Carmen Moccia ◽

Kristina Haase

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Triple Negative ◽

New Drugs ◽

Patient Specific ◽

Preclinical Models ◽

Cancer Subtypes ◽

On Chip

Breast cancer is the second leading cause of death among women worldwide, and while hormone receptor positive subtypes have a clear and effective treatment strategy, other subtypes, such as triple negative breast cancers, do not. Development of new drugs, antibodies, or immune targets requires significant re-consideration of current preclinical models, which frequently fail to mimic the nuances of patient-specific breast cancer subtypes. Each subtype, together with the expression of different markers, genetic and epigenetic profiles, presents a unique tumor microenvironment, which promotes tumor development and progression. For this reason, personalized treatments targeting components of the tumor microenvironment have been proposed to mitigate breast cancer progression, particularly for aggressive triple negative subtypes. To-date, animal models remain the gold standard for examining new therapeutic targets; however, there is room for in vitro tools to bridge the biological gap with humans. Tumor-on-chip technologies allow for precise control and examination of the tumor microenvironment and may add to the toolbox of current preclinical models. These new models include key aspects of the tumor microenvironment (stroma, vasculature and immune cells) which have been employed to understand metastases, multi-organ interactions, and, importantly, to evaluate drug efficacy and toxicity in humanized physiologic systems. This review provides insight into advanced in vitro tumor models specific to breast cancer, and discusses their potential and limitations for use as future preclinical patient-specific tools.

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Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression

10.1101/085316 ◽

2016 ◽

Author(s):

Nao Hiranuma ◽

Jie Liu ◽

Chaozhong Song ◽

Jacob Goldsmith ◽

Michael Dorschner ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative ◽

The Cancer Genome Atlas ◽

Breast Cancers ◽

Single Nucleotide Variants ◽

Primary Tumors ◽

Cancer Subtypes ◽

Multiple Biopsies ◽

Cancer Genome Atlas

About 16% of breast cancers fall into a clinically aggressive category designated triple negative (TNBC) due to a lack of ERBB2, estrogen receptor and progesterone receptor expression1-3. The mutational spectrum of TNBC has been characterized as part of The Cancer Genome Atlas (TCGA)4; however, snapshots of primary tumors cannot reveal the mechanisms by which TNBCs progress and spread. To address this limitation we initiated the Intensive Trial of OMics in Cancer (ITOMIC)-001, in which patients with metastatic TNBC undergo multiple biopsies over space and time5. Whole exome sequencing (WES) of 67 samples from 11 patients identified 426 genes containing multiple distinct single nucleotide variants (SNVs) within the same sample, instances we term Multiple SNVs affecting the Same Gene and Sample (MSSGS). We find that >90% of MSSGS result from cis-compound mutations (in which both SNVs affect the same allele), that MSSGS comprised of SNVs affecting adjacent nucleotides arise from single mutational events, and that most other MSSGS result from the sequential acquisition of SNVs. Some MSSGS drive cancer progression, as exemplified by a TNBC driven by FGFR2(S252W;Y375C). MSSGS are more prevalent in TNBC than other breast cancer subtypes and occur at higher-than-expected frequencies across TNBC samples within TCGA. MSSGS may denote genes that play as yet unrecognized roles in cancer progression.

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Effect of CCL2 on survival of breast cancer MDA-MB-231 cells via inhibition of apoptosis

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22176 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22176-e22176

Author(s):

A. S. Alva ◽

Z. Varsos ◽

H. Roca ◽

K. Pienta

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Neutralizing Antibodies ◽

Response To Treatment ◽

Primary Breast Tumor ◽

Antibody Array ◽

Human Antibody ◽

Endogenous Expression ◽

Expression Of Genes ◽

And Migration

e22176 Background: The cytokine CCL2 (Chemokine (C-C) motif ligand 2 or monocyte chemo attractant protein-1 MCP-1) has been shown to play an important role in breast cancer progression by promoting angiogenesis and migration. CCL2 is over-expressed by breast cancer cells as well as by macrophages and mesenchymal stem cells in the tumor micro-environment. We studied the effects of CCL2 and IL-6 on survival of breast cancer MDA-MB-231 cells. Methods: Cytokine expression including of CCL2 and IL- 6 were analyzed in supernatants from MDA-MB-231 cells using cytokine antibody array (Human Antibody Array 3; Ray Biotech, Inc). Serum starved MDA-MB-231 cells were treated with CCL2 (75 ng/mL) and IL-6 (100 ng/mL; both from Apollo Cytokine Research). Cell viability in response to treatment was analyzed at serial time points by cell proliferation assay WST-1 (Roche Applied Science). Protein expression of genes of interest was studied by Western blot. Results: In contrast to primary breast tumor cells, MDA-MB-231 cells express minimal CCL2 at baseline. MDA-MB-231 cells also exhibit low expression of IL-6. Stimulation of MDA-MB-231 cells with either exogenous CCL2 or exogenous IL-6 did not increase levels of the other cytokine. In MDA-MB-231 cells, CCL2, alone and in combination with IL-6, promotes survival in serum starved conditions. Treatment of MDA-MB-231 cells with CCL2 leads to survivin up-regulation beginning at 48 hours as determined by immunoblotting analysis. CCL2 in combination with IL-6 inhibits the cleavage of PARP, lamin and caspase3. Conclusions: There is minimal endogenous expression of CCL2 in MDA-MB-231 cells. CCL2 from the tumor micro-environment promotes survival of MDA-MB-231 cells associated with up-regulation of survivin. IL-6 may play a syngeristic role with CCL2 in promoting survival of MDA-MB-231 cells. We plan to explore the role of survivin up-regulation in protecting cells from cell death. Our findings raise the possibility of utilizing neutralizing antibodies against CCL2 in therapy of breast cancer. No significant financial relationships to disclose.

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Expression of Annexin A2 Promotes Cancer Progression in Estrogen Receptor Negative Breast Cancers

Cells ◽

10.3390/cells9071582 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1582 ◽

Cited By ~ 2

Author(s):

Amira F. Mahdi ◽

Beatrice Malacrida ◽

Joanne Nolan ◽

Mary E. McCumiskey ◽

Anne B. Merrigan ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Lines ◽

Cancer Progression ◽

Annexin A2 ◽

Breast Cancer Progression ◽

Migration And Invasion ◽

Breast Cancer Cell Lines ◽

Cancer Subtypes ◽

Estrogen Receptor Negative

When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.

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Blood Genome-Wide Transcriptional Profiles of HER2 Negative Breast Cancers Patients

Mediators of Inflammation ◽

10.1155/2016/3239167 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Ovidiu Balacescu ◽

Loredana Balacescu ◽

Oana Virtic ◽

Simona Visan ◽

Claudia Gherman ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative ◽

Transcriptional Analysis ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Cancer Subtypes ◽

Her2 Breast Cancer ◽

Adaptive Immune Cells

Tumors act systemically to sustain cancer progression, affecting the physiological processes in the host and triggering responses in the blood circulating cells. In this study, we explored blood transcriptional patterns of patients with two subtypes of HER2 negative breast cancers, with different prognosis and therapeutic outcome. Peripheral blood samples from seven healthy female donors and 29 women with breast cancer including 14 triple-negative breast cancers and 15 hormone-dependent breast cancers were evaluated by microarray. We also evaluated the stroma in primary tumors. Transcriptional analysis revealed distinct molecular signatures in the blood of HER2− breast cancer patients according to ER/PR status. Our data showed the implication of immune signaling in both breast cancer subtypes with an enrichment of these processes in the blood of TNBC patients. We observed a significant alteration of “chemokine signaling,” “IL-8 signaling,” and “communication between innate and adaptive immune cells” pathways in the blood of TNBC patients correlated with an increased inflammation and necrosis in their primary tumors. Overall, our data indicate that the presence of triple-negative breast cancer is associated with an enrichment of altered systemic immune-related pathways, suggesting that immunotherapy could possibly be synergistic to the chemotherapy, to improve the clinical outcome of these patients.

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Association of CYP19A1 gene variants with differences in disease progression in breast cancer patients from different racial/ethnic backgrounds.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1558 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1558-1558

Author(s):

Reina Villareal ◽

Angela W. Meisner ◽

Lina Aguirre ◽

Vibhati Kulkarny ◽

Vallabh Shah ◽

...

Keyword(s):

Breast Cancer ◽

Disease Progression ◽

Cancer Patients ◽

Racial Differences ◽

Cancer Progression ◽

Allele Frequencies ◽

Response To Treatment ◽

Gene Variants ◽

Breast Cancer Patients ◽

Genotype Frequencies

1558 Background: Polymorphisms in the aromatase (CYP19A1) gene result in differences in the risk for breast cancer and response to treatment. We hypothesize that allele frequencies in the CYP19A1 gene vary according to race and may result in differences in progression of breast cancer among women from different racial backgrounds. The objectives of this study are: 1) to determine the allele/genotype frequencies in the CYP19A1 gene among women with breast cancer from different racial backgrounds, and, 2) to determine the association between disease progression and CYP19A1 gene variants. Methods: Clinical data and stored DNA from 327 patients participating in the Expanded Breast Cancer Registry (EBCR) program at the University of New Mexico were analyzed. These patients were followed-up for a period of 1 to 6 years. Comprehensive genotyping for CYP19A1 gene single nucleotide polymorphisms (SNPs) was performed using microarray (Illumina). Results: Data from 164 non-Hispanic white and 119 Hispanic women were analyzed. Four SNPs (rs1259269, rs17703883, rs16964211, rs28757101) were associated with differences in genotype/allele frequencies between the 2 racial groups. Furthermore, 3 SNPs (rs4646, rs17647478, and rs6493486) were associated with differences in disease progression. The rare allele (G) for the rs17647478 (G/T) is associated with poor progression compared those without the allele (41.7% vs. 17.1%, p=0.04). Similarly the minor (A) allele for the rs4646 (A/C) and the rs6493486 (A/G) is also associated with a greater chance of worsening disease (23.2% vs. 12.4%, p=0.02 and 23.4% vs. 12.4%, p=0.02, respectively). A significant percentage of women carrying the A allele for both rs4646 and rs6493486 and the T allele for the rs17647478 have more advanced disease at the time of presentation. None of the SNPs analyzed result in racial differences in breast cancer progression. Conclusions: Polymorphisms in the CYP19A1 gene influence overall disease progression in breast cancer patients but have no impact on the racial differences of disease behavior. Women carrying the risk alleles present at a more advanced stage and are also at greater risk of progression.

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Targeting the polyamine pathway—“a means” to overcome chemoresistance in triple-negative breast cancer

Journal of Biological Chemistry ◽

10.1074/jbc.h120.013736 ◽

2020 ◽

Vol 295 (19) ◽

pp. 6278-6279 ◽

Cited By ~ 1

Author(s):

Colleen Sweeney

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

De Novo ◽

Poor Survival ◽

Polyamine Synthesis ◽

Cancer Subtypes ◽

Highly Sensitive ◽

Resistance To Chemotherapy ◽

New Strategies

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

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Metabolomic profiling of mouse mammary tumor derived cell lines reveals targeted therapy options for cancer subtypes

10.1101/796573 ◽

2019 ◽

Cited By ~ 1

Author(s):

Martin P. Ogrodzinski ◽

Sophia Y. Lunt

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Cell Lines ◽

Metabolic Pathways ◽

Tricarboxylic Acid Cycle ◽

Treatment Strategies ◽

Nucleotide Metabolism ◽

Glutathione Metabolism ◽

Therapy Options ◽

Cancer Subtypes

AbstractBreast cancer is a heterogeneous disease with several subtypes that currently do not have targeted therapy options. Metabolomics has the potential to uncover novel targeted treatment strategies by identifying metabolic pathways required for cancer cells to survive and proliferate. Here, we used tumor-derived cell lines derived from the MMTV-Myc mouse model to investigate metabolic pathways that are differentially utilized between two subtypes of breast cancer. Using mass spectrometry-based metabolomics techniques, we identified differences in glycolysis, the tricarboxylic acid cycle, glutathione metabolism, and nucleotide metabolism between subtypes. We further show the feasibility of targeting these pathways in a subtype-specific manner using metabolism-targeting compounds.

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