COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice

Gonçalves, Rosângela Mayer; Delgobo, Marina; Agnes, Jonathan Paulo; Neves, Raquel Nascimento das; Falchetti, Marcelo; Casagrande, T. S.; Vargas, Ana Paula; Vieira, Thaynan Cunha; Somensi, Nauana; Bruxel, Maciel Alencar; Mendes, Dayse; Rafacho, Alex; Báfica, André; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca; Cassali, Geovanni Dantas; Bishop, Alexander J.R.; Zanotto-Filho, Alfeu

doi:10.1016/j.canlet.2021.01.003

Cited by 27 publications

(18 citation statements)

References 60 publications

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“…Because estrogen synthesis is significantly enhanced by a high-fat diet ( 22 ), we speculate that the effects of ANGPTL8 in promoting ectopic deposition of lipids induced by HFD in female mice were counteracted by inhibition of its expression by estrogen. We performed OVX on female mice to induce estrogen deficiency ( Figure 5F ).…”

Section: Resultsmentioning

confidence: 99%

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

Tang

Gao

et al. 2022

Front. Endocrinol.

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BackgroundEctopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.MethodsWe used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.ResultsANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.ConclusionsANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

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Section: Resultsmentioning

confidence: 99%

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

Tang

Gao

et al. 2022

Front. Endocrinol.

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“…The production of PGE2 depends on inducible cyclooxygenase-2 (COX-2), and the mRNA level of COX2 correlates with the expression of aromatase [ 80 ]. A more recent study showed that treatment with a COX-2 selective inhibitor etoricoxib reduced the aromatase protein and estrogen levels and decreased the incidence of mammary tumors in high-sugar/fat-fed mice [ 81 ]. In a mouse model of postpartum breast cancer whereby the invasiveness of tumor cells is dependent on COX-2, ibuprofen treatment mitigated the increased tumor growth, decreased lung metastasis, and restored COX-2 expression to the level found in nulliparous counterparts [ 82 ].…”

Section: Estrogen Inflammation and Breast Cancermentioning

confidence: 99%

Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer

Maharjan

Wang

et al. 2021

Cancers

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The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen’s pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.

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“…The increase in fat mass and aromatase may be responsible for the increased risk of HR+ BC in postmenopausal obese women. High-sugar/fat diet increased the levels of pro-inflammatory mediators CCL2, IL-6, COX-2, and PGE2 in breast tissue, accompanied by the formation of breast coronal structure and the up-regulated biosynthesis of aromatase/estrogen ( 78 ). It showed that the obesogenic diet accelerated BC carcinogenesis in a COX-2-dependent manner.…”

Section: Mechanisms Linking Obesity and Breast Cancermentioning

confidence: 99%

Current Landscape: The Mechanism and Therapeutic Impact of Obesity for Breast Cancer

Zhao

et al. 2021

Front. Oncol.

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Obesity is defined as a chronic disease induced by an imbalance of energy homeostasis. Obesity is a widespread health problem with increasing prevalence worldwide. Breast cancer (BC) has already been the most common cancer and one of the leading causes of cancer death in women worldwide. Nowadays, the impact of the rising prevalence of obesity has been recognized as a nonnegligible issue for BC development, outcome, and management. Adipokines, insulin and insulin-like growth factor, sex hormone and the chronic inflammation state play critical roles in the vicious crosstalk between obesity and BC. Furthermore, obesity can affect the efficacy and side effects of multiple therapies such as surgery, radiotherapy, chemotherapy, endocrine therapy, immunotherapy and weight management of BC. In this review, we focus on the current landscape of the mechanisms of obesity in fueling BC and the impact of obesity on diverse therapeutic interventions. An in-depth exploration of the underlying mechanisms linking obesity and BC will improve the efficiency of the existing treatments and even provide novel treatment strategies for BC treatment.

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COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice

Cited by 27 publications

References 60 publications

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer

Current Landscape: The Mechanism and Therapeutic Impact of Obesity for Breast Cancer

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