Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer

Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)–dependent manner, which signals through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation. Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness. Moreover, weight loss reverses the effects of obesity on MMe macrophage inflammation and TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue as a mechanism for promoting TNBC stemness and tumorigenesis during obesity.

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Metabolically activated macrophages in mammary adipose tissue link obesity to triple-negative breast cancer

10.1101/370627 ◽

2018 ◽

Author(s):

Payal Tiwari ◽

Ariane Blank ◽

Chang Cui ◽

Kelly Q. Schoenfelt ◽

Guolin Zhou ◽

...

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Tumor Formation ◽

List Type ◽

Dependent Manner ◽

Macrophage Phenotype ◽

Adipose Tissue Macrophages

SUMMARYObesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Macrophages, which accumulate in adipose tissue and are activated during obesity, are an attractive mechanistic link. Here, we show that, during obesity, murine and human mammary adipose tissue macrophages adopt a pro-inflammatory, metabolically- activated (MMe) macrophage phenotype that promotes TNBC stem-like markers and functions, including increased tumorsphere growthin vitroand tumor-initiating potentialin vivo. We demonstrate that MMe macrophages release cytokines in an NADPH oxidase 2 (NOX2)-dependent manner that signal through glycoprotein 130 (GP130) on TNBC cells to promote their stem-like properties. Accordingly, deletingNox2in myeloid cells or depleting GP130 in TNBC cells attenuates the ability of obesity to drive TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue during obesity as a mechanism for promoting TNBC stemness and tumorigenesis.HIGHLIGHTS⁘Obesity promotes TNBC tumor formation and stemness.⁘Mammary adipose tissue macrophages are metabolically activated (MMe) in obese mice and humans.⁘MMe macrophages in mammary adipose tissue contribute to obesity-induced stemness.⁘MMe macrophages promote TNBC stemness through GP130 signaling.

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Use of Proton Pump Inhibitors as Adjunct Treatment for Triple-Negative Breast Cancers. An Introductory Study

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j34608 ◽

2014 ◽

Vol 17 (3) ◽

pp. 439 ◽

Cited By ~ 29

Author(s):

Wayne Goh ◽

Inna Sleptsova-Freidrich ◽

Nenad Petrovic

Keyword(s):

Breast Cancer ◽

Cancer Treatment ◽

Cancer Cells ◽

Proton Pump ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Dependent Manner ◽

Breast Cancers ◽

Gastric Type ◽

Dose Dependent

PURPOSE: Triple negative breast cancers (estrogen, progesterone and human epidermal growth factor 2 (HER2) receptor-negative) are among the most aggressive forms of cancers with limited treatment options. Doxorubicin is one of the agents found in many of the current cancer treatment protocols, although its use is limited by dose-dependent cardiotoxicity. This work investigates one of the ways to suppress cancer growth by inhibiting tumor cell ability to remove acid accumulated during its metabolism by proton pump inhibitor esomeprazole (a drug with extensive clinical use) which could serve as an addition to doxorubicin therapy. METHODS: In this work, we have investigated growth suppression of triple-negative breast cancer cells MDA-MB-468 by esomeprazole and doxorubicin by trypan blue exclusion assay. Measurement of acidification of treated cancer cells was performed using intracellular pH-sensitive probe, BCECF-AM. Finally, expression of gastric type proton pump (H+/K+ ATPase, a target for esomeprazole) on MDA-MB-468 cells was detected by immunofluorescence and Western blotting. RESULTS: We have found that esomeprazole suppresses growth of triple-negative breast cancer cell in vitro in a dose-dependent manner through increase in their intracellular acidification. In contrast, esomeprazole did not have significant effect on non-cancerous breast epithelial MCF-10A cells. Esomeprazole increases doxorubicin effects suggesting that dual treatments might be possible. In addition, response of MDA-MB-468 cells to esomeprazole could be mediated by gastric type proton pump (H+/K+ ATPase) in cancer cells contrary to previous beliefs that this proton pump expression is restricted to parietal cells of the stomach epithelia. CONCLUSION: This study provides first evidence that adjunct use of esomeprazole in breast cancer treatment might be a possible to combat adverse effects of doxorubicin and increase its effectiveness. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Meroterpenoids From Ganoderma lucidum Mushrooms and Their Biological Roles in Insulin Resistance and Triple-Negative Breast Cancer

Frontiers in Chemistry ◽

10.3389/fchem.2021.772740 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jiao-Jiao Zhang ◽

Dai-Wei Wang ◽

Dan Cai ◽

Qing Lu ◽

Yong-Xian Cheng

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Cell Line ◽

Triple Negative Breast Cancer ◽

Ganoderma Lucidum ◽

Triple Negative ◽

Raw Materials ◽

Biological Evaluation ◽

C2c12 Cells ◽

Dependent Manner

Ganoderma fungi as popular raw materials of numerous functional foods have been extensively investigated. In this study, five pairs of meroterpenoid enantiomers beyond well-known triterpenoids and polysaccharides, dayaolingzhiols I−M (1–5), were characterized from Ganoderma lucidum. Their structures were identified using spectroscopic and computational methods. Structurally, compound 1 features a novel dioxabicyclo[2.2.2]octan-3-one motif in the side chain. Ethnoknowledge-derived biological evaluation found that (+)-5 could activate Akt and AMPK phosphorylation in insulin-stimulated C2C12 cells, and (+)-5 could activate glucose uptake dose dependently in C2C12 cells. Furthermore, we found that (+)-1 (+)-4, and (–)-4 could significantly inhibit cell migration of the MDA-MB-231 cell line, of which (+)-4 showed significant inhibitory effects against cell migration of the MDA-MB-231 cell line in a dose-dependent manner. These findings revealed the meroterpenoidal composition of G. lucidum and its roles in the prevention of chronic diseases such as diabetes mellitus and triple-negative breast cancer.

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Inhibition of LIPG phospholipase activity suppresses tumor formation of human basal-like triple-negative breast cancer

Scientific Reports ◽

10.1038/s41598-020-65400-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Pang-Kuo Lo ◽

Yuan Yao ◽

Qun Zhou

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Tumor Formation ◽

Phospholipase Activity

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CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1

Cell Death and Disease ◽

10.1038/s41419-021-04114-8 ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Hong Luo ◽

Zhicheng Zhou ◽

Shan Huang ◽

Mengru Ma ◽

Manyu Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Triple Negative Breast Cancer ◽

Fatty Acid Synthase ◽

Triple Negative ◽

Trichostatin A ◽

Affinity Purification ◽

Negative Regulator ◽

Dependent Manner ◽

Breast Cancers

AbstractFailures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

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St. John’s Wort Suppresses Growth in Triple-Negative Breast Cancer Cell Line MDA-MB-231 by Inducing Prodeath Autophagy and Apoptosis

Nutrients ◽

10.3390/nu12103175 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3175

Author(s):

Mikyoung You ◽

Young-Hyun Lee ◽

Hwa-Jin Kim ◽

Ji Hyun Kook ◽

Hyeon-A Kim

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cell Line ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Apoptotic Cell ◽

Cancer Cell Line ◽

Dependent Manner ◽

St John’S Wort ◽

St John's Wort

The rational regulation of programmed cell death by means of autophagy and apoptosis has been considered a potential treatment strategy for cancer. We demonstrated the inhibitory effect of St. John’s Wort (SJW) on growth in the triple-negative breast cancer (TNBC) cell line and xenografted mice and its target mechanism concerning autophagic and apoptotic cell death. SJW ethanol extract (SJWE) inhibited proliferation in a dose-dependent manner. SJWE treatment dramatically increased autophagy flux and apoptosis compared with the control. The autophagy inhibitor, 3-methyladenine (3-MA), reversed the SJWE-induced inhibition of cell proliferation and regulation of autophagy and apoptosis, indicating that SJWE induced apoptosis through prodeath autophagy. Furthermore, SJWE inhibited tumor growth and induced autophagy and apoptosis in the tumor of MDA-MB-231 xenografted athymic nude mice. Our results indicate that SJWE might have great potential as a new anticancer therapy for triple-negative breast cancer by inducing prodeath autophagy and apoptosis.

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The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers12092455 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2455

Author(s):

Augustus M. C. Tilley ◽

Cory M. Howard ◽

Sangita Sridharan ◽

Boopathi Subramaniyan ◽

Nicole R. Bearss ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Chemokine Receptor ◽

Cancer Metastasis ◽

Triple Negative ◽

Receptor Type ◽

Proximity Ligation Assay ◽

Dependent Manner ◽

Invasive Ability ◽

Matrigel Invasion

The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the CXCR4 signaling pathway, as its deficiency blocks CXCR4-dependent Matrigel invasion. The mechanism by which LASP1 facilitates this invasive ability of tumor cells when CXCR4 is activated is unknown. Our previous proteomics work had revealed several components of the RNA interference (RNAi) machinery as being potential LASP1 interacting proteins. Here we report that argonaute 2 (Ago2), a protein with central involvement in RNAi, associates with LASP1 in triple-negative breast cancer (TNBC) cells. We demonstrate that LASP1 co-immunoprecipitates with Ago2 endogenously in a CXCL12-dependent manner, with further confirmation of this interaction by proximity ligation assay. Furthermore, this association is specific to CXCR4 as it can be abrogated by the CXCR4 antagonist, AMD3465. By GST-pulldown approach, we identify that LASP1 directly binds to Ago2 through its LIM and SH3 domains, and that this binding is dictated by the S146 and Y171 phosphorylation sites of LASP1. Additionally, the phosphorylation status of LASP1 affected tumor suppressor microRNA (miRNA) Let-7a-guided Ago2 activity. Levels of several endogenous targets of Let-7a were found to be altered including C-C chemokine receptor type 7 (CCR7), which is another critical chemokine receptor involved in metastasis to lymph nodes. Our results suggest a novel role for the LASP1-Ago2 module in shaping the RNAi landscape, functionally impacting the invasive ability of cancer cells.

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A Polyphenol Rich Muscadine Grape Extract Reduces Triple Negative Breast Cancer Cell Migration in Association with Changes in Cell Morphology and Motility-Related Proteins

Current Developments in Nutrition ◽

10.1093/cdn/nzaa044_024 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 325-325

Author(s):

Patricia Gallagher ◽

Marianne Collard ◽

Heather Brown-Harding ◽

Elisabeth Tallant

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Confocal Microscopy ◽

Triple Negative Breast Cancer ◽

Cell Shape ◽

Molecular Mechanisms ◽

Triple Negative ◽

Dependent Manner ◽

Grape Extract ◽

Muscadine Grape

Abstract Objectives Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen receptors, progesterone receptors and over-expression of the human epidermal growth factor receptor 2, limiting targeted treatment. TNBC disproportionally affects ethnic minorities and younger women and has a high propensity to metastasize, often within 5 years of diagnosis, making it one of the most aggressive breast cancer subtypes. We showed that treatment with a proprietary muscadine grape extract (MGE) reduced the growth and metastasis of TNBC in mice. Muscadine grapes (V. Rotundifolia) are rich in polyphenols and extracts produced from muscadine grape seed and skin are marketed as nutraceuticals for their anti-oxidant, anti-inflammatory, and anti-cancer properties. The goal of these studies was to determine the molecular mechanisms for the reduction in metastatic growth by MGE. Methods A proprietary extract was prepared from muscadine grape seeds and skins. Migration of MDA-MB-231 and BT-549 cells was measured by a scratch wound assay, cell shape was visualized by confocal microscopy and mRNA/proteins that participate in cell migration/motility were measured by RT-PCR and western blot hybridization. Results The extract reduced the migration of MDA-MB-231 and BT-549 TNBC cells in a dose-dependent manner. The reduction in cell migration was associated with MGE-induced alterations in cell shape and actin filament organization, visualized by confocal microscopy. The extract caused an apparent loss of cell polarization in MDA-MB-231 cells and a reduction in the presence of filopodia in BT-549 cells. The MGE-induced reduction in migration and alterations in cell shape and polarization were associated with a decrease in Rho kinase ROCK1/2 mRNA and protein as well as both the mRNA and protein expression of RHAMM, a protein that is implicated in both cell motility and breast cancer progression. Conclusions These results demonstrate that a proprietary MGE reduces TNBC cell migration, in association with changes in cell shape and cytoskeleton as well as proteins that regulate migration and motility, suggesting that treatment of TNBC patients with MGE may slow or prevent metastatic progression. Funding Sources Chronic Disease Research Fund.

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ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

Science Signaling ◽

10.1126/scisignal.abb9820 ◽

2020 ◽

Vol 13 (658) ◽

pp. eabb9820 ◽

Cited By ~ 1

Author(s):

Peter Cruz-Gordillo ◽

Megan E. Honeywell ◽

Nicholas W. Harper ◽

Thomas Leete ◽

Michael J. Lee

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Apoptotic Cell ◽

Growth Factor Receptor ◽

Similar Degree ◽

Dependent Manner ◽

Egfr Signaling ◽

Egfr Inhibition ◽

A Genome

Targeted therapeutics for cancer generally exploit “oncogene addiction,” a phenomenon in which the growth and survival of tumor cells depend on the activity of a particular protein. However, the efficacy of oncogene-targeted therapies varies substantially. For instance, targeting epidermal growth factor receptor (EGFR) signaling is effective in some non–small cell lung cancer (NSCLC) but not in triple-negative breast cancer (TNBC), although these cancers show a similar degree of increase in EGFR activity. Using a genome-wide CRISPR-Cas9 genetic knockout screen, we found that the Elongator (ELP) complex mediates insensitivity to the EGFR inhibitor erlotinib in TNBC cells by promoting the synthesis of the antiapoptotic protein Mcl-1. Depleting ELP proteins promoted apoptotic cell death in an EGFR inhibition–dependent manner. Pharmacological inhibition of Mcl-1 synergized with EGFR inhibition in a panel of genetically diverse TNBC cells. The findings indicate that TNBC “addiction” to EGFR signaling is masked by the ELP complex and that resistance to EGFR inhibitors in TNBC might be overcome by cotargeting Mcl-1.

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