TAp73 represses NF-κB–mediated recruitment of tumor-associated macrophages in breast cancer

Infiltration of tumor-promoting immune cells is a strong driver of tumor progression. Especially the accumulation of macrophages in the tumor microenvironment is known to facilitate tumor growth and to correlate with poor prognosis in many tumor types. TAp73, a member of the p53/p63/p73 family, acts as a tumor suppressor and has been shown to suppress tumor angiogenesis. However, what role TAp73 has in regulating immune cell infiltration is unknown. Here, we report that low levels of TAp73 correlate with an increased NF-κB–regulated inflammatory signature in breast cancer. Furthermore, we show that loss of TAp73 results in NF-κB hyperactivation and secretion of Ccl2, a known NF-κB target and chemoattractant for monocytes and macrophages. Importantly, TAp73-deficient tumors display an increased accumulation of protumoral macrophages that express the mannose receptor (CD206) and scavenger receptor A (CD204) compared to controls. The relevance of TAp73 expression in human breast carcinoma was further accentuated by revealing that TAp73 expression correlates negatively with the accumulation of protumoral CD163+ macrophages in breast cancer patient samples. Taken together, our findings suggest that TAp73 regulates macrophage accumulation and phenotype in breast cancer through inhibition of the NF-κB pathway.

Download Full-text

Faculty Opinions recommendation of Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725485692.793517744 ◽

2016 ◽

Author(s):

Paul Timpson ◽

Claire Vennin

Keyword(s):

Breast Cancer ◽

Human Breast Cancer ◽

Immune Cell ◽

Cancer Invasion ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Human Breast ◽

Breast Cancer Invasion

Download Full-text

Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer

Cancers ◽

10.3390/cancers12051325 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1325 ◽

Cited By ~ 1

Author(s):

Patrice M. Witschen ◽

Thomas S. Chaffee ◽

Nicholas J. Brady ◽

Danielle N. Huggins ◽

Todd P. Knutson ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Chronic Wound ◽

Gene Signature ◽

Tumor Formation ◽

Human Breast ◽

Inflammatory Microenvironment ◽

Tumor Types

Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation of an inflammatory microenvironment. Our results demonstrate that breast cancer cells synthesize and fragment HA and express CD44 on the cell surface. Using RNA sequencing approaches, we found that loss of CD44 in breast cancer cells altered the expression of cytokine-related genes. Specifically, we found that production of the chemokine CCL2 by breast cancer cells was significantly decreased after depletion of either CD44 or HA. In vivo, we found that CD44 deletion in breast cancer cells resulted in a delay in tumor formation and localized progression. This finding was accompanied by a decrease in infiltrating CD206+ macrophages, which are typically associated with tumor promoting functions. Importantly, our laboratory results were supported by human breast cancer patient data, where increased HAS2 expression was significantly associated with a tumor promoting inflammatory gene signature. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.

Download Full-text

Breast tumor IGF-1R regulates cell adhesion and metastasis: Alignment of mouse single cell and human breast cancer transcriptomics

10.1101/2021.08.31.458283 ◽

2021 ◽

Author(s):

Alison E Obr ◽

Yung-Jun Chang ◽

Virginia Ciliento ◽

Alexander Lemenze ◽

Krystopher Maingrette ◽

...

Keyword(s):

Breast Cancer ◽

Tyrosine Kinases ◽

Immune Cell ◽

Patient Survival ◽

Patient Data ◽

Critical Event ◽

Breast Cancers ◽

Human Breast ◽

Metastatic Phenotype ◽

Human Patient

The acquisition of a metastatic phenotype is the critical event that determines patient survival from breast cancer. Several receptor tyrosine kinases have functions both in promoting and inhibiting metastasis in breast tumors. Although the insulin-like growth factor 1 receptor (IGF-1R) has been considered a target for inhibition in breast cancer, low levels of IGF-1R expression are associated with worse overall patient survival. To determine how reduced IGF-1R impacts tumor phenotype, we used weighted correlation gene network analysis (WCGNA) of METABRIC patient data and identified gene modules specific to cell cycle, adhesion, and immune cell signaling inversely correlated with IGF-1R expression in human breast cancers. Integration of human patient data with data from mouse tumors revealed similar pathways necessary for promoting metastasis in basal-like tumors with reduced signaling or expression of the IGF-1R. Functional analyses revealed the basis for the enhanced metastatic phenotype including alterations in E- and P-cadherins.

Download Full-text

Tissue Factor Expression during Monocyte-Macrophage Differentiation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656125 ◽

1997 ◽

Vol 77 (06) ◽

pp. 1129-1136 ◽

Cited By ~ 16

Author(s):

Mark M E D van den Eijnden ◽

Sari-lrina Steenhauer ◽

Pieter H Reitsma ◽

Rogier M Bertina

Keyword(s):

Tissue Factor ◽

Scavenger Receptor ◽

Mannose Receptor ◽

Factor Vii ◽

Macrophage Differentiation ◽

Factor Expression ◽

Monocytes And Macrophages ◽

High Affinity Receptor ◽

Affinity Receptor ◽

Spontaneous Expression

SummaryTissue factor (TF), the high affinity receptor and cofactor of factor VII, is considered as the main procoagulant in stimulated monocytes and macrophages. We studied the effect of longterm culture (differentiation) on “spontaneous” and induced (LPS) expression of TF (mRNA, antigen, cell surface associated Vlla-cofactor activity) in isolated human monocytes.TF was expressed transiently in monocytes cultured on Teflon membranes (suspension monocytes, Mo-S) and on plastic dishes (adherent monocytes, Mo-A), reaching maximal levels between days 3 and 5. Increased expression of TF was accompanied by increased stable expression of macrophage specific markers (CD71, the mannose receptor, the scavenger receptor).Bacterial lipopolysaccharide (LPS) induced (additional) TF mRNA, antigen, and activity in both Mo-S and Mo-A. In Mo-S and Mo-A of days 3 to 5, the period in which there was “spontaneous” expression of TF, TF response to LPS was considerably lower.It is concluded that during monocyte-macrophage transition, TF is “spontaneously” and transiently expressed and that with respect to TF induction the responsiveness of the cells to LPS is maintained.

Download Full-text

IL-6 influences PD-L1 expression in monocytes and macrophages by effecting protein tyrosine phosphatase receptor type O expression in-human breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15570 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15570-e15570

Author(s):

Lin Chen ◽

Jinhai Tang

Keyword(s):

Breast Cancer ◽

T Cells ◽

Protein Tyrosine Phosphatase ◽

Human Breast Cancer ◽

Tyrosine Phosphatase ◽

Receptor Type ◽

Human Breast ◽

Protein Tyrosine ◽

Monocytes And Macrophages

e15570 Background: We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human breast cancer (BC). Methods: The expression and correlation of all the indices were explored in monocytes and tumor infiltrating macrophages within both human and mice BC. The mechanic regulations were studied by using both in vitro and in vivo studies. Results: We found a significant decrease in PTPRO in BC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in BC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with BC and were associated with increased T cell exhaustion (Tim3+ T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25-3p axis. Monocytes and TAMs showed significantly increased miR-25-3p expression, which could target the 3' untranslated region of PTPRO. The miR-25-3p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in BC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25-3p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25-3p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in breast tumor model. Conclusions: Increased serum IL-6 downregulated PTPRO expression in BC monocytes and macrophages by activating STAT3/c-MYC/miR-25-3p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.

Download Full-text

Multi-Omics Reveals the Immunological Role and Prognostic Potential of Mitochondrial Ubiquitin Ligase MARCH5 in Human Breast Cancer

Biomedicines ◽

10.3390/biomedicines9101329 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1329

Author(s):

Pei-Yi Chu ◽

Yen-Dun Tony Tzeng ◽

Yi-Han Chiu ◽

Hung-Yu Lin ◽

Chen-Hsin Kuo ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Immunity ◽

Ubiquitin Ligase ◽

Immune Cell ◽

Human Breast ◽

Immune Markers ◽

Normal Tissues ◽

Diagnosis And Prognosis ◽

Highly Correlated ◽

The Relationship

E3 ubiquitin-linked enzyme MARCH5, also known as membrane-associated circular finger 5, is an enzyme encoded by the human MARCH5 gene. The main objective of this study was to visualize the prognosis of MARCH5 in breast cancer and to determine the relationship between MARCH5 expression and tumor immunity. MARCH5 expression was significantly higher in several cancers, including breast cancer (BRCA), compared with corresponding normal tissues. Not only was high MARCH5 expression associated with poorer overall survival, but also MARCH5 expression was positively correlated with the number of tumor-infiltrating immune cells in BRCA malignant tissues. Furthermore, MARCH5 expression showed a strong correlation with various immune markers of BRCA, suggesting its role in regulating tumor immunity. MARCH5 is a useful prognostic biomarker in several cancers, and its expression is highly correlated with tumor immune cell infiltration, and increased MARCH5 expression may serve as a new biomarker for BRCA diagnosis and prognosis.

Download Full-text

Clinical Relevance of Estrogen Reactivity in the Breast Cancer Microenvironment

10.21203/rs.3.rs-671517/v1 ◽

2021 ◽

Author(s):

Takashi Takeshita ◽

Tomohiro Oshino ◽

Yoshihisa Tokumaru ◽

Masanori Oshi ◽

Ankit Patel ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Immune Cell ◽

Cytolytic Activity ◽

University Hospital ◽

Gene Sets ◽

Response To Chemotherapy ◽

Mtorc1 Signaling ◽

Low Levels ◽

Cell Stress Response

Abstract Background: Estrogen signals play an important role in the phenotype of estrogen receptor positive breast cancer (BC). However, comprehensive analyses of the effect of estrogen signals on the tumor microenvironment (TME) and treatment response in large cohorts of primary BC patients have been lacking. We aimed to test the hypothesis that estrogen reactivity effects gene expression and immune cell infiltration profiles in the TME and relates to response to chemotherapy (CT) and endocrine therapy (ET). Methods: A total of 3091 BC cases were analyzed; 1075 from TCGA cohort, 1904 from METABRIC cohort, and 112 from Hokkaido University hospital cohort. We divided the group into estrogen reactivity-high and estrogen reactivity-low groups utilizing estrogen response genes.Results: BC with high estrogen reactivity was related to Myc targets, Metabolism-related signaling, cell stress response, TGF-beta signaling, androgen response, and MTORC1 signaling gene sets in the TME. Low estrogen reactivity was related to immune-related proteins, IL2-STAT5 signaling, IL6-JAK-STAT3 signaling, KRAS signaling, cell cycle related gene sets, and EMT. In addition, BC with high levels of estrogen reactivity had low immune cytolytic activity, low levels of immunostimulatory cells, and high levels of immunosuppressive cells. It also had low levels of stimulatory and inhibitory factors of the cancer immunity cycle (CIC). Patients with high estrogen reactivity were also associated with a better prognosis. Regarding the effect of estrogen reactivity on treatment, patients who were treated with ET and CT but relapsed (BC with CT rec) were related with higher levels of E2F targets and G2M checkpoint, but lower levels of immunosuppressive M2 macrophages or Tregs cells. In addition, the TME in CT rec had higher levels of CIC regulators.Conclusions: We demonstrated the relationship between estrogen reactivity and the profiles of immune cells and gene expression within the TME, as well as the treatment effect of CT given in addition to ET.

Download Full-text