HDL of Patients with Type 2 Diabetes Mellitus Elevates the Capability of Promoting Breast Cancer Metastasis

Pan, Bing; Ren, Hui; He, Yanni; Lv, Xiaoyi; Ma, Yijing; Li, Jing; Huang, Li Chi; Yu, Baoqi; Kong, Jian; Niu, Chenguang; Zhang, Youyi; Sun, Wenbing; Zheng, Lemin

doi:10.1158/1078-0432.ccr-11-0817

Cited by 49 publications

(33 citation statements)

References 48 publications

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“…This phenotype includes increased migratory capacity, invasiveness, resistance to apoptosis, and elevated production of extracellular matrix (ECM) components (Kalluri and Weinberg 2009; Thiery 2002). In many carcinomas, growth factors such as transforming growth factor-beta (TGFB) and epidermal growth factor (EGF), can lead to the induction of EMT signals by increasing the gene expression of various EMT-inducing transcription factors; most commonly SNAIL, SLUG, zinc finger E-box binding homeobox 1 (ZEB1), and TWIST1 (Al Moustafa, et al 2012; Kim, et al 2002; Niessen, et al 2008; Pan, et al 2012; Shi and Massague 2003; Spaderna, et al 2008). The data presented in this study is the first to our knowledge to show that hyperinsulinemia increases the expression of several EMT genes in vivo.…”

Section: Discussionmentioning

confidence: 99%

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

Zelenko

Gallagher

Antoniou

et al. 2016

Endocrine-Related Cancer

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Type 2 Diabetes (T2D) is associated with increased cancer risk and cancer-related mortality. Data herein show that we generated an immunodeficient hyperinsulinemic mouse by crossing the Rag1−/− mice, which have no mature B or T lymphocytes, with the MKR mouse model of T2D to generate the Rag1−/− (Rag/WT) and Rag1−/−/MKR+/+ (Rag/MKR) mice. The female Rag/MKR mice are insulin resistant and have significantly higher non-fasting plasma insulin levels compared to the Rag/WT controls. Therefore, we used these Rag/MKR mice to investigate the role of endogenous hyperinsulinemia on human cancer progression. In this study we show that hyperinsulinemia in the Rag/MKR mice increases the expression of mesenchymal transcription factors, TWIST1 and ZEB1, and increases the expression of the angiogenesis marker, vascular endothelial growth factor A (VEGFA). We also show that silencing the insulin receptor (IR) in the human LCC6 cancer cells leads to decreased tumor growth and metastases, suppression of mesenchymal markers Vimentin, SLUG, TWIST1, and ZEB1, suppression of angiogenesis markers, VEGFA and VEGFD, and re-expression of the epithelial marker, E-cadherin. The data in this paper demonstrate that IR knockdown in primary tumors partially reverses the growth promoting effects of hyperinsulinemia as well as highlighting the importance of the insulin receptor signaling pathway in cancer progression, and more specifically in epithelial-mesenchymal transition.

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Section: Discussionmentioning

confidence: 99%

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

Zelenko

Gallagher

Antoniou

et al. 2016

Endocrine-Related Cancer

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“…SR-BI contributes to the tumor development and malignant processes and studies have proposed a role for SR-BI in breast cancer and as novel therapeutic aim. 7,43 There are multiple mechanisms thought to be involved in the altered serum cholesterol concentrations in cancer, including the upregulation of LDL receptors in metastatic cells as a result of enhanced cholesterol catabolism, [44][45][46] heightened storage of esterified cholesterol in cancer cells, and increased usage of cholesterol in case of newly synthesized membranes. [37][38][39] The level of SR-BI receptor expression in aggressive tumors has been found to be increased compared with the normal cells.…”

Section: Metabolism Of Cholesterol In Breast Cancermentioning

confidence: 99%

High‐density lipoprotein functionality and breast cancer: A potential therapeutic target

Samadi

Mobarhan

Mohammadpour

et al. 2018

J of Cellular Biochemistry

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Breast cancer is a major cause of death globally, and particularly in developed countries. Breast cancer is influenced by cholesterol membrane content, by affecting the signaling pathways modulating cell growth, adherence, and migration. Furthermore, steroid hormones are derived from cholesterol and these play a key role in the pathogenesis of breast cancer. Although most findings have reported an inverse association between serum high‐density lipoprotein (HDL)‐cholesterol level and the risk of breast cancer, there have been some reports of the opposite, and the association therefore remains unclear. HDL is principally known for participating in reverse cholesterol transport and has an inverse relationship with the cardiovascular risk. HDL is heterogeneous, with particles varying in composition, size, and structure, which can be altered under different circumstances, such as inflammation, aging, and certain diseases. It has also been proposed that HDL functionality might have a bearing on the breast cancer. Owing to the potential role of cholesterol in cancer, its reduction using statins, and particularly as an adjuvant during chemotherapy may be useful in the anticancer treatment, and may also be related to the decline in cancer mortality. Reconstituted HDLs have the ability to release chemotherapeutic drugs inside the cell. As a consequence, this may be a novel way to improve therapeutic targeting for the breast cancer on the basis of detrimental impacts of oxidized HDL on cancer development.

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“…In vivo works have suggested that hypercholesterolemia induced by diet and/or genetic background leads to increased tumor burden and metastasis in murine breast cancer models [10,12]. In vitro analyses have shown that human breast cancer cell lines exhibit increased proliferation and migration in the presence of HDL [11,13,15-17]. The effect of cholesterol on breast cancer may be attributed to several of its properties and functions.…”

Section: Introductionmentioning

confidence: 99%

Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development

et al. 2013

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IntroductionPrevious studies have identified cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, the scavenger receptor class B type I (SR-BI) have both been implicated in the regulation of cellular cholesterol homeostasis, but their functions in cancer remain to be established.MethodsIn the present study, we have examined the role of HDL and SR-BI in the regulation of cellular signaling pathways in breast cancer cell lines and in the development of tumor in a mouse xenograft model.ResultsOur data show that HDL is capable of stimulating migration and can activate signal transduction pathways in the two human breast cancer cell lines, MDA-MB-231 and MCF7. Furthermore, we also show that knockdown of the HDL receptor, SR-BI, attenuates HDL-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (Akt) pathway in both cell lines. Additional investigations show that inhibition of the PI3K pathway, but not that of the mitogen-activated protein kinase (MAPK) pathway, could lead to a reduction in cellular proliferation in the absence of SR-BI. Importantly, whereas the knockdown of SR-BI led to decreased proliferation and migration in vitro, it also led to a significant reduction in tumor growth in vivo. Most important, we also show that pharmacological inhibition of SR-BI can attenuate signaling and lead to decreased cellular proliferation in vitro. Taken together, our data indicate that both cholesteryl ester entry via HDL-SR-BI and Akt signaling play an essential role in the regulation of cellular proliferation and migration, and, eventually, tumor growth.ConclusionsThese results identify SR-BI as a potential target for the treatment of breast cancer.

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HDL of Patients with Type 2 Diabetes Mellitus Elevates the Capability of Promoting Breast Cancer Metastasis

Cited by 49 publications

References 48 publications

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

High‐density lipoprotein functionality and breast cancer: A potential therapeutic target

Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development

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