Leptin induces ROS via NOX5 in healthy and neoplastic mammary epithelial cells

Mahbouli, Sinda; Vartanian, Audrey Der; Ortega, Sophie; Rouge, Stéphanie; Vasson, Marie‐Paule; Rossary, Adrien

doi:10.3892/or.2017.6009

Cited by 35 publications

(24 citation statements)

References 53 publications

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“…In breast cancer, leptin has been proposed to have a role at different levels (45, 46). At a carcinogenic level, it has been suggested to act as a direct potential activator of short term ROS production in human epithelial mammary cells (47), although other studies previously showed that chronic leptin treatment decreases ROS levels and oxidative stress in MCF-7 cells (48). According to the trophic function of leptin, demonstrated also in MCF7 cells (49), it seems to regulate metabolic reprogramming to promote cellular growth (50).…”

Section: Leptin and Breast Cancermentioning

confidence: 99%

Obesity and Breast Cancer: Role of Leptin

et al. 2019

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Obesity-related breast cancer is an important threat that affects especially post-menopausal women. The link between obesity and breast cancer seems to be relying on the microenvironment generated at adipose tissue level, which includes inflammatory cytokines. In addition, its association with systemic endocrine changes, including hyperinsulinemia, increased estrogens levels, and hyperleptinemia may be key factors for tumor development. These factors may promote tumor initiation, tumor primary growth, tissue invasion, and metastatic progression. Although the relationship between obesity and breast cancer is already established, the different pathophysiological mechanisms involved are not clear. Obesity-related insulin resistance is a well-known risk factor for breast cancer development in post-menopausal women. However, the role of inflammation and other adipokines, especially leptin, is less studied. Leptin, like insulin, appears to be a growth factor for breast cancer cells. There exists a link between leptin and metabolism of estrogens and between leptin and other factors in a more complex network. As a result, obesity-associated hyperleptinemia has been suggested as an important mediator in the pathophysiology of breast cancer. On the other hand, recent data on the paradoxical effect of obesity on cancer immunotherapy efficacy has brought some controversy, since the proinflammatory effect of leptin may help the effect of immune checkpoint inhibitors. Therefore, a better knowledge of the molecular mechanisms that mediate leptin action may be helpful to understand the underlying processes which link obesity to breast cancer in post-menopausal women, as well as the possible role of leptin in the response to immunotherapy in obese patients.

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Section: Leptin and Breast Cancermentioning

confidence: 99%

Obesity and Breast Cancer: Role of Leptin

et al. 2019

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“…67 It also activates ROS production in human epithelial mammary cells. 90 Leptin also regulates metabolic reprogramming which promotes cellular growth. 91 All these will modify the microenvironment at adipose tissue that will promote breast cancer development.…”

Section: The Link Between Leptin and Breast Cancermentioning

confidence: 99%

Linkage Between Obesity Leptin and Breast Cancer

Atoum

Alzoughool

Al-Hourani

2020

Breast Cancer�(Auckl)

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Many cancers might be influenced by obesity, including breast cancer, the leading cause of cancer death among women. Obesity is a complex state associated with multiple physiological and molecular changes capable of modulating the behavior of breast tumor cells and the surrounding microenvironment. This review discussed the inverse association between obesity and breast cancer among premenopausal breast cancer females and the positive association among postmenopausal. Four mechanisms may link obesity and breast cancer including leptin and leptin receptor expression, adipose chronic inflammation, sex hormone alternation, and insulin and insulinlike growth factor 1 (IGF-1) signaling. Leptin has been involved in breast cancer initiation, development, and progression through signaling transduction network. Leptin functions are strengthened through cross talk with multiple oncogenes, cytokines, and growth factors. Adipose chronic inflammation promotes cancer growth and angiogenesis and modifies the immune responses. A pro-inflammatory microenvironment at tumor site promotes cytokines and pro-inflammatory mediators adjacent to the tumor. Leptin stimulates pro-inflammatory cytokines and promotes T-helper 1 responses. Obesity is common of chronic inflammation. In obese patients, white adipose tissue (WAT) will promote pro-inflammatory mediators that will encourage tumor growth and WAT inflammation. Sex hormone alternation of estrogens is associated with increased risk for hormone-sensitive breast cancers. Estrogens cause tumorigenesis by its effect on signaling pathways that lead to DNA damage, stimulation angiogenesis, mutagenesis, and cell proliferation. In postmenopausal females, and due to termination of ovarian function, estrogens were produced extra gonadally, mainly in peripheral adipose tissues where adrenal-produced androgen precursors are converted to estrogens. Active estradiol leads to breast cancer development by binding to ERα, which is modified by receptor’s interaction of various signal transduction pathways. Hyperinsulinemia and IGF-1 activate the MAPK and PI3K pathways, leading to cancer-promoting effects. Cross talk between insulin/IGF and estrogen signaling pathways promotes hormone-sensitive breast cancer development. Hyperinsulinemia is a risk factor for breast cancer that explains the obesity-breast cancer association. Controlling IGF-1 level and targeting IGF-1 receptors among different breast cancer subtypes may be useful for breast cancer treatment. This review discussed several leptin signaling pathways, highlighting the potential advantage of targeting leptin as a potential target of the novel therapeutic strategies for breast cancer treatment.

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“…NOX5 has also been demonstrated in many non‐immune cells and tissues, including placenta, bone marrow, uterus, stomach, skeletal muscle, cancer cells and hepatocytes and in cells of the cardiovascular system, such as cardiomyocytes, endothelial and vascular smooth muscle cells (Mahbouli et al., ; Montezano et al., ; Yeung et al., ). The functional significance of this widespread expression profile suggests that NOX5 is likely to be important in many (patho)physiological processes in multiple systems that involve ROS.…”

Section: Expression Of Nox5 In Physiological and Pathological Conditionsmentioning

confidence: 99%

NOX5: Molecular biology and pathophysiology

Touyz

Anagnostopoulou

Ríos

et al. 2019

Experimental Physiology

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New Findings What is the topic of this review? This review provides a comprehensive overview of Nox5 from basic biology to human disease and highlights unique features of this Nox isoform What advances does it highlight? Major advances in Nox5 biology relate to crystallization of the molecule and new insights into the pathophysiological role of Nox5. Recent discoveries have unravelled the crystal structure of Nox5, the first Nox isoform to be crystalized. This provides new opportunities to develop drugs or small molecules targeted to Nox5 in an isoform‐specific manner, possibly for therapeutic use. Moreover genome wide association studies (GWAS) identified Nox5 as a new blood pressure‐associated gene and studies in mice expressing human Nox5 in a cell‐specific manner have provided new information about the (patho) physiological role of Nox5 in the cardiovascular system and kidneys. Nox5 seems to be important in the regulation of vascular contraction and kidney function. In cardiovascular disease and diabetic nephropathy, Nox5 activity is increased and this is associated with increased production of reactive oxygen species and oxidative stress implicated in tissue damage. Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), comprise seven family members (Nox1–Nox5 and dual oxidase 1 and 2) and are major producers of reactive oxygen species in mammalian cells. Reactive oxygen species are crucially involved in cell signalling and function. All Noxs share structural homology comprising six transmembrane domains with two haem‐binding regions and an NADPH‐binding region on the intracellular C‐terminus, whereas their regulatory systems, mechanisms of activation and tissue distribution differ. This explains the diverse function of Noxs. Of the Noxs, NOX5 is unique in that rodents lack the gene, it is regulated by Ca 2+ , it does not require NADPH oxidase subunits for its activation, and it is not glycosylated. NOX5 localizes in the perinuclear and endoplasmic reticulum regions of cells and traffics to the cell membrane upon activation. It is tightly regulated through numerous post‐translational modifications and is activated by vasoactive agents, growth factors and pro‐inflammatory cytokines. The exact pathophysiological significance of NOX5 remains unclear, but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation, and NOX5 hyperactivation has been implicated in cardiovascular disease, kidney injury and cancer. The field of NOX5 biology is still in its infancy, but with new insights into its biochemistry and cellular regulation, discovery of the NOX5 crystal structure and genome‐wide association studies implicating NOX5 in disease, the time is now ripe to advance NOX5 research. This review provides a comprehensive overview of our current understanding of NOX5, from basic ...

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Leptin induces ROS via NOX5 in healthy and neoplastic mammary epithelial cells

Cited by 35 publications

References 53 publications

Obesity and Breast Cancer: Role of Leptin

Obesity and Breast Cancer: Role of Leptin

Linkage Between Obesity Leptin and Breast Cancer

NOX5: Molecular biology and pathophysiology

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