HDL and LDL: Potential New Players in Breast Cancer Development.

Breast cancer is the most prevalent cancer and primary cause of cancer-related mortality in women. The identification of risk factors can improve prevention of cancer, and obesity and hypercholesterolemia represent potentially modifiable breast cancer risk factors. In the present work, we review the progress to date in research on the potential role of the main cholesterol transporters, low-density and high-density lipoproteins (LDL and HDL), on breast cancer development. Although some studies have failed to find associations between lipoproteins and breast cancer, some large clinical studies have demonstrated a direct association between LDL cholesterol levels and breast cancer risk and an inverse association between HDL cholesterol and breast cancer risk. Research in breast cancer cells and experimental mouse models of breast cancer have demonstrated an important role for cholesterol and its transporters in breast cancer development. Instead of cholesterol, the cholesterol metabolite 27-hydroxycholesterol induces the proliferation of estrogen receptor-positive breast cancer cells and facilitates metastasis. Oxidative modification of the lipoproteins and HDL glycation activate different inflammation-related pathways, thereby enhancing cell proliferation and migration and inhibiting apoptosis. Cholesterol-lowering drugs and apolipoprotein A-I mimetics have emerged as potential therapeutic agents to prevent the deleterious effects of high cholesterol in breast cancer

Lipid-Laden Macrophages and Inflammation in Atherosclerosis and Cancer : An Integrative View

Altres ajuts: Wihuri Foundation; Pulsus Foundation.Atherosclerotic arterial plaques and malignant solid tumors contain macrophages, which participate in anaerobic metabolism, acidosis, and inflammatory processes inherent in the development of either disease. The tissue-resident macrophage populations originate from precursor cells derived from the yolk sac and from circulating bone marrow-derived monocytes. In the tissues, they differentiate into varying functional phenotypes in response to local microenvironmental stimulation. Broadly categorized, the macrophages are activated to polarize into proinflammatory M1 and anti-inflammatory M2 phenotypes; yet, noticeable plasticity allows them to dynamically shift between several distinct functional subtypes. In atherosclerosis, low-density lipoprotein (LDL)-derived cholesterol accumulates within macrophages as cytoplasmic lipid droplets thereby generating macrophage foam cells, which are involved in all steps of atherosclerosis. The conversion of macrophages into foam cells may suppress the expression of given proinflammatory genes and thereby initiate their transcriptional reprogramming toward an anti-inflammatory phenotype. In this particular sense, foam cell formation can be considered anti-atherogenic. The tumor-associated macrophages (TAMs) may become polarized into anti-tumoral M1 and pro-tumoral M2 phenotypes. Mechanistically, the TAMs can regulate the survival and proliferation of the surrounding cancer cells and participate in various aspects of tumor formation, progression, and metastasis. The TAMs may accumulate lipids, but their type and their specific roles in tumorigenesis are still poorly understood. Here, we discuss how the phenotypic and functional plasticity of macrophages allows their multifunctional response to the distinct microenvironments in developing atherosclerotic lesions and in developing malignant tumors. We also discuss how the inflammatory reactions of the macrophages may influence the development of atherosclerotic plaques and malignant tumors, and highlight the potential therapeutic effects of targeting lipid-laden macrophages in either disease

Cholesterol Efflux and Reverse Cholesterol Transport

Both alterations of lipid/lipoprotein metabolism and inflammatory events contribute to the formation of the atherosclerotic plaque, characterized by the accumulation of abnormal amounts of cholesterol and macrophages in the artery wall. Reverse cholesterol transport (RCT) may counteract the pathogenic events leading to the formation and development of atheroma, by promoting the high-density lipoprotein (HDL)-mediated removal of cholesterol from the artery wall. Recent in vivo studies established the inverse relationship between RCT efficiency and atherosclerotic cardiovascular diseases (CVD), thus suggesting that the promotion of this process may represent a novel strategy to reduce atherosclerotic plaque burden and subsequent cardiovascular events. HDL plays a primary role in all stages of RCT: (1) cholesterol efflux, where these lipoproteins remove excess cholesterol from cells; (2) lipoprotein remodeling, where HDL undergo structural modifications with possible impact on their function; and (3) hepatic lipid uptake, where HDL releases cholesterol to the liver, for the final excretion into bile and feces. Although the inverse association between HDL plasma levels and CVD risk has been postulated for years, recently this concept has been challenged by studies reporting that HDL antiatherogenic functions may be independent of their plasma levels. Therefore, assessment of HDL function, evaluated as the capacity to promote cell cholesterol efflux may offer a better prediction of CVD than HDL levels alone. Consistent with this idea, it has been recently demonstrated that the evaluation of serum cholesterol efflux capacity (CEC) is a predictor of atherosclerosis extent in humans

ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk, but several epidemiologic studies have reported contradictory results with regard to the relationship between apolipoprotein (apo) A-I and breast cancer. We aimed to determine the effects of human apoA-I overexpression and administration of specific apoA-I mimetic peptide (D-4F) on tumour progression by using mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice as a model of inherited breast cancer. Expression of human apoA-I in the mice did not affect tumour onset and growth in PyMT transgenic mice, despite an increase in the HDLc level. In contrast, D-4F treatment significantly increased tumour latency and inhibited the development of tumours. The effects of D-4F on tumour development were independent of 27-hydroxycholesterol. However, D-4F treatment reduced the plasma oxidized low-density lipoprotein (oxLDL) levels in mice and prevented oxLDL-mediated proliferative response in human breast adenocarcinoma MCF-7 cells. In conclusion, our study shows that D-4F, but not apoA-I-containing HDL, hinders tumour growth in mice with inherited breast cancer in association with a higher protection against LDL oxidative modification.This work was partly funded by Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III: FIS PI11/01076 (to F.V-B.), PI12/00291 (to J.C.E-G.) and PI13/02507 (to A.C.), and RETIC RIC RD12/0042/0055 (to A.C.); by Ministerio de Economía y Competitividad, SAF2011-23402 (to A.F.V); by an intramural project of the Institut de Recerca de l’Hospital de la Santa Creu I Sant Pau (IR15-P5); and by grant from the Academy of Finland #257545 (to M.J.). CIBER de Diabetes y Enfermedades Metabólicas Asociadas is an Instituto de Salud Carlos III Project. A.M.F. and S.T.R. were funded by HL-30568 and by a Leducq Foundation Network grant, and J.M.C. is an APIF fellowship recipient (Universitat de Barcelona).Peer Reviewe

Modulation of autoimmune arthritis severity in mice by Apolipoprotein E (ApoE) and cholesterol

Apolipoprotein E (ApoE) deficiency promoted an exacerbation of autoimmune arthritis in mice by inducing pro-inflammatory immune responses. In this study we analysed the contribution of hypercholesterolemia and/or the absence of ApoE anti-inflammatory properties, unrelated to its function in the control of cholesterol metabolism, towards the acceleration of arthritis in these mutant animals. The induction and severity of collagen type II-induced arthritis (CIA) were compared for B10.RIII wild type (WT), B10.RIII.ApoE+/- , B10.RIII.ApoE-/- and B10.RIII.LDLR-/- mice with different concentrations of circulating ApoE and cholesterol. A 50-70% reduction in serum levels of ApoE was observed in heterozygous B10.RIII.ApoE+/- mice in comparison to B10.RIII.WT, although both strains of mice exhibited similar circulating lipid profiles. This ApoE reduction was associated with an increased CIA severity that remained lower than in homozygous B10.RIII.ApoE-/- mice. An important rise in circulating ApoE concentration was observed in hypercholesterolemic B10.RIII.LDLR-/- mice fed with a normal chow diet, and both parameters further increased with an atherogenic hypercholesterolemic diet. However the severity of CIA in B10.RIII.LDLR-/- mice was similar to that of B10.RIII.WT controls. In conclusion, by comparing the evolution of CIA between several strains of mutant mice with different levels of serum ApoE and cholesterol, our results demonstrate that both hypercholesterolemia and ApoE regulate the intensity of in vivo systemic autoimmune responses. This article is protected by copyright. All rights reserve

MiR-125b downregulates macrophage scavenger receptor type B1 and reverse cholesterol transport

Objective: To determine whether miR-125b regulates cholesterol efflux in vivo and in vitro through the regulation of scavenger receptor type B1 (SR-B1). Approach and results: We demonstrated that miR-125b is up-regulated in the human aortas of patients with CAD and is located in macrophages and vascular smooth muscle cells (VSMCs). We identified SCARB1 as a direct target of miR-125b by repressing the activity of the SCARB1 3'-untranslated region reporter construct. Moreover, the overexpression of miR-125b in both human and mouse macrophages as well as VSMCs was found to downregulated the expression of the SCARB1 and the SR-B1 protein levels, thereby impairing alpha-HDL-mediated macrophage cholesterol efflux in vitro. The in vivo reverse cholesterol transport (RCT) rate from non-cholesterol-loaded macrophages transfected with miR-125b to feces was also found to be decreased when compared with that of control mimic-transfected macrophages. Conclusions: Together, these results provide evidence that miR-125b downregulates SCARB1 and SR-B1 in both human and mouse macrophages as well as VSMCs, thereby impairing macrophage cholesterol efflux in vitro and the whole macrophage-specific RCT pathway in vivo

Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia

The accumulation of lipids in cardiomyocytes contributes to cardiac dysfunction. The specific blockage of cardiomyocyte cholesteryl ester (CE) loading by antibodies (Abs) against the P3 sequence (Gly-Cys) of the LRP1 receptor improves cardiac insulin sensitivity. The impact of anti-P3 Abs on high-fat diet (HFD)-induced cardiac extracellular matrix (ECM) biophysical alterations was analyzed. Both IrP (without Abs) and P3-immunized rabbits (with Abs) were randomized into groups fed either HFD or a standard chow diet. Cardiac lipids, proteins, and carbohydrates were characterized by Fourier transform infrared spectroscopy in the attenuated total reflectance mode. The hydric organization and physical structure were determined by differential scanning calorimetry. HFD increased the levels of esterified lipids, collagen, and α-helical structures and upregulated fibrosis, bound water, and ECM plasticization in the heart. The inhibitory effect of anti-P3 Abs on cardiac CE accumulation was sufficient to reduce the collagen-filled extracellular space, the level of fibrosis, and the amount of bound water but did not counteract ECM plasticization in the heart of hypercholesterolemic rabbits.The economic support to develop this project was received from Fundació MARATÓ TV3 with Grant 201521-10 (to V.L.-C.), FIS PI21/01523 (to V.L.-C.) from the Instituto de Salud Carlos III (ISCIII) and co-financed with ERDFs, and Fundación BBVA Ayudas a equipos de investigación 2019. This work was also funded by the Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC) Grants PROYECTOS CONSOLIDAR 2018–2021 (to G.C.), Fondo para la Investigación Científica y Tecnológica (FONCyT), and Préstamo BID Proyecto de Investigación en Ciencia y Tecnología (PICT) Grants 2015-0807 and 2017-4497 (to G.C.). Support was received from the Albert Renold Travel Fellowship Programme 2019 from the European Foundation of the study of Diabetes (EFSD) and the Wood-Whelan fellowship Programme 2019 from the International Union of Biochemistry and Molecular Biology (IUBMB) to cover the stay of V.A.D. in Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC) and Biomedical Research Institute Sant Pau (IIB Sant Pau). V.A.D. is a postdoctoral fellow of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI). A.B.-A. is a predoctoral fellow (FI19/00205) granted by the Programme _Contratos predoctorales de formación de investigación en salud_ from the Instituto de Salud Carlos III (ISCIII) and co-financed with ERDFs. Our group is part of CIBER Enfermedades Cardiovasculares (CIBERCV; CB16/11/00276 to J.M.G. and V.L.-C.) and CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM; CB07/08/0016 to J.C.E.-G.), projects run by the Instituto de Salud Carlos III. Our group also participates in Redes de investigación (Enfermedades Metabóloicas y Cáncer RED2018-102799-T), a project run by MINECO. The V.L.-C. group is recognized by Generalitat de Catalunya (2017 SGR 946). The authorsd thank Eva Prats and the staff from Centres Científics i Tecnològics de la Universitat de Barcelona (Campus Casanova) (CCiT/UB) for sample processing for electron microscopy. The IR-SANTPAU is a center of CERCA Programme/Generalitat de Catalunya

La inmunoterapia basada en LRP1 como estrategia eficaz para inhibir las alteraciones metabólicas en el sistema cardiovascular

Trabajo presentado en el Congreso SEC de la Salud Cardiovascular, celebrado en Mallorca (España), del 20 al 22 de octubre de 2022Background: Antibodies against the P3 sequence (Gly1127-Cys1140) of LRP1 (anti-P3 Abs) specifically block cholesteryl ester (CE) accumulation in vascular cells. LRP1 is a key regulator of insulin receptor (InsR) trafficking in different cell types. The link between CE accumulation and the insulin response are largely unknown. Here, the effects of P3 peptide immunization on the alterations induced by a high-fat diet (HFD) in cardiac insulin response were evaluated. Methods: Irrelevant (IrP)- or P3 peptide-immunized rabbits were randomized into groups fed either HFD or normal chow. Cardiac lipid content was characterized by thin-layer chromatography, confocal microscopy, and electron microscopy. LRP1, InsR and glucose transporter type 4 (GLUT4) levels were determined in membranes and total lysates from rabbit heart. The interaction between InsR and LRP1 was analyzed by immunoprecipitation and confocal microscopy. Insulin signaling activity and glucose uptake were evaluated in HL-1 cells exposed to rabbit serum from the different groups. Findings: HFD reduces cardiac InsR and GLUT4 membrane levels and the interactions between LRP1/InsR. Targeting the P3 sequence on LRP1 through anti-P3 Abs specifically reduces CE accumulation in the heart independently of changes in the circulating lipid profile. This restores InsR and GLUT4 levels in cardiac membranes as well as the LRP1/InsR interactions of HFD-fed rabbits. In addition, anti-P3 Abs restores the insulin signaling cascade and glucose uptake in HL-1 cells exposed to hypercholesterolemic rabbit serum