High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells

Flores-López, Luis Antonio; Martínez-Hernández, María Guadalupe; Viedma‐Rodríguez, Rubí; Díaz‐Flores, Margarita; Baiza-Gutman, Luís Arturo

doi:10.1007/s13402-016-0282-8

Cited by 62 publications

(45 citation statements)

References 76 publications

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“…Diabetes itself might have a direct effect on breast cancer prognosis due to physiological effects of hyperglycemia, or hyperinsulinemia, which is a hallmark of insulin resistance commonly observed in patients with type 2 diabetes [28,29]. It has been shown that cancer-specific survival was decreased for women with abnormal glycemic status [25,27] and that fasting insulin levels are associated with worse outcome (distant recurrence and death), independent of Body Mass Index (BMI) [30].…”

Section: Introductionmentioning

confidence: 99%

Diabetes and Breast Cancer Subtypes

et al. 2017

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BackgroundWomen with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes.Methods and FindingsThis cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000–2010. Stratified by age at breast cancer diagnosis (≤50 and >50 years), women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories) to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR), HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211) and women without diabetes (n = 101), irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%CI:1.07–5.55)), HER2-negative (OR = 2.84(95%CI:1.11–7.22)), and basal-like (OR = 3.14(95%CI:1.03–9.60) tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95–6.45)) and triple negative (OR = 2.60(95%CI:0.88–7.67) tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general.ConclusionsWe found no compelling evidence that women with diabetes, treated with or without insulin, develop different breast cancer subtypes than women without diabetes. However, premenopausal women with diabetes tended to develop breast tumors that do not express hormonal receptors, which are typically associated with poor prognosis.

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Section: Introductionmentioning

confidence: 99%

Diabetes and Breast Cancer Subtypes

et al. 2017

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“…PAI‐1 is expressed in mature TGCs in vivo (Teesalu, Blasi, & Talarico, ) and in vitro (Harvey et al, ). Increased levels of PAI‐1 expression have been associated with increased invasiveness of cancer cells (Flores‐López, Martinez‐Hernandez, Viedma‐Rodriguez, Diaz‐Flores, & Baiza‐Gutman, ; Kwaan, Mazar, & McMahon, ). According to our results, HG enhances the expression levels of PLAU, MMP‐9, and PAI‐1 in several cancer cell lines, and these proteins have been correlated with higher migratory and invasive ability (Flores‐López et al, ; Lin et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Increased levels of PAI‐1 expression have been associated with increased invasiveness of cancer cells (Flores‐López, Martinez‐Hernandez, Viedma‐Rodriguez, Diaz‐Flores, & Baiza‐Gutman, ; Kwaan, Mazar, & McMahon, ). According to our results, HG enhances the expression levels of PLAU, MMP‐9, and PAI‐1 in several cancer cell lines, and these proteins have been correlated with higher migratory and invasive ability (Flores‐López et al, ; Lin et al, ). Trophoblast and tumor cells have similar characteristics, including the increased expression of proteases that may play active roles in migration and invasion (Ferretti, Bruni, Dangles‐Marie, Pecking, & Bellet, ).…”

Section: Discussionmentioning

confidence: 99%

“…NAC is also a precursor of an endogenous reducing agent glutathione, the principal intracellular antioxidant. NAC prevents the HG‐induced stress in different cell types and decreases PLAU expression and activity in several contexts (Kim, Kim, Na, & Surh, ; Tobar, Villar, & Santibañez, ), including HG (Flores‐López et al, ). The action of NAC is likely dependent on the glucose concentration.…”

Section: Discussionmentioning

confidence: 99%

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Hyperglycemia‐induced mouse trophoblast spreading is mediated by reactive oxygen species

Sánchez-Santos

Martínez-Hernández

Contreras-Ramos³

et al. 2018

Molecular Reproduction Devel

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During embryo implantation, the outer layer of the blastocyst interacts with the endometrium giving rise to the development of the trophoblast cell lineage. The cells in this lineage participate in the penetration of endometrium due to their motility and invasive properties. The mechanisms that regulate the differentiation and invasive ability of these cells are essential for the establishment and maintenance of an efficient exchange between maternal and fetal tissues during pregnancy. In this context, hyperglycemia can induce oxidative stress causing alterations in the placenta. This study evaluated the role of reactive oxygen species (ROS) in the actions of high glucose concentration (HG) on trophoblast spreading and the expression of extracellular proteases in cultured mouse conceptuses. Blastocysts from gestational day 4 (GD4) were cultured until GD7 in HAM-F10 medium and further treated for 48 hr with HG (25 mM glucose) from GD7 to GD9. This treatment induced larger trophoblast outgrowths and increased ROS concentration, which was associated with increased expression levels of urokinase-type plasminogen activator (PLAU), plasminogen activator inhibitor 1 (PAI-1), and matrix metalloproteinase 9 (MMP-9). These effects were prevented by treatment with the non-specific antioxidant N-acetylcysteine (NAC) or apocynin, an inhibitor of NADPH oxidase. Our data suggest that the HG-induced trophoblast spreading and the expression of PLAU, PAI-1, and MMP-9 were mediated by the production of ROS via NADPH oxidase activity. Our results shed light on placental alterations in gestational diabetes mellitus.

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“…23 Increased expression of ROS is found in most of cancers including the breast cancer cells. 24 While the increased expression of ROS is observed in cancer cells, recent studies show an interesting observation that the cancer stem cells have reduced expression of ROS. 25 With less ROS, cancer stem cells can evade the ROS mediated apoptosis, which makes them to survive better than cancer cells.…”

Section: Ros and Cancermentioning

confidence: 99%

Role of oxidative stress in facilitating carcinogenesis

Natarajan

2017

Int J Res Med Sci

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The carcinogenic role of ROS has been a great debate in the past and will be in the future. ROS is produced by both internal (inflammation) and external sources (UV). ROS is important for various important signalling mechanisms for the normal cellular survival. Even though literature exists to support the role of ROS in cancer, the magnitude of its expression and cell type it is expressed will determine whether it plays a positive (apoptosis) or negative role (genomic instability) in cancer. Apart from inducing DNA damage, ROS facilitates carcinogenesis by regulating cell cycle progression, gap junction, inflammation etc. The present review updates the recent discoveries of how ROS regulates these important cellular signalling mechanisms to facilitate carcinogenesis.

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High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells

Cited by 62 publications

References 76 publications

Diabetes and Breast Cancer Subtypes

Diabetes and Breast Cancer Subtypes

Hyperglycemia‐induced mouse trophoblast spreading is mediated by reactive oxygen species

Role of oxidative stress in facilitating carcinogenesis

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