Expression of the Lipid Transporters ABCA3 and ABCA1 is Diminished in Human Breast Cancer Tissue

Schimanski, Sven; Wild, Peter J.; Treeck, Oliver; Horn, F.; Sigrüener, Alexander; Rudolph, Colin; Blaszyk, Hagen; Klinkhammer‐Schalke, Monika; Ortmann, O.; Hartmann, Anne; Schmitz, Gerd

doi:10.1055/s-0029-1241859

Cited by 61 publications

(55 citation statements)

References 19 publications

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“…All statistical comparisons are to the corresponding "scr" exposure control. mediated death in cancer cells by increasing mitochondrial cholesterol (41), and it has been proposed that this finding could underlie other recent reports linking ABCA1 deficiency to cancer (42,43). Given this, some of the targets we found increased in Abca1 Ϫ/Ϫ DRMs may possibly underlie the cancer cell survival advantage recently associated with ABCA1 deficiency.…”

Section: Discussionsupporting

confidence: 79%

Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling

Chowdhury¹,

Zhu

Aloor³

et al. 2015

Molecular & Cellular Proteomics

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Lipid raft membrane microdomains organize signaling by many prototypical receptors, including the Toll-like receptors (TLRs) of the innate immune system. Raft-localization of proteins is widely thought to be regulated by raft cholesterol levels, but this is largely on the basis of studies that have manipulated cell cholesterol using crude and poorly specific chemical tools, such as ␤-cyclodextrins. To date, there has been no proteome-scale investigation of whether endogenous regulators of intracellular cholesterol trafficking, such as the ATP binding cassette (ABC)A1 lipid efflux transporter, regulate targeting of proteins to rafts. Abca1 ؊/؊ macrophages have cholesterolladen rafts that have been reported to contain increased levels of select proteins, including TLR4, the lipopolysaccharide receptor. Here, using quantitative proteomic profiling, we identified 383 proteins in raft isolates from Abca1 ؉/؉ and Abca1 ؊/؊ macrophages. ABCA1 deletion induced wide-ranging changes to the raft proteome. Remarkably, many of these changes were similar to those seen in Abca1 ؉/؉ macrophages after lipopolysaccharide exposure. Stomatin-like protein (SLP)-2, a member of the stomatin-prohibitin-flotillin-HflK/C family of membrane scaffolding proteins, was robustly and specifically increased in Abca1 ؊/؊ rafts. Pursuing SLP-2 function, we found that rafts of SLP-2-silenced macrophages had markedly abnormal composition. SLP-2 silencing did not compromise ABCA1-dependent cholesterol efflux but reduced macrophage responsiveness to multiple TLR ligands. This was associated with reduced raft levels of the TLR co-receptor, CD14, and defective lipopolysaccharide-induced recruitment of the common TLR adaptor, MyD88, to rafts. Taken together, we show that the lipid transporter ABCA1 regulates the protein repertoire of rafts and identify SLP-2 as an ABCA1-dependent regulator of raft composition and of the innate immune response. Molecular & Cellular

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Section: Discussionsupporting

confidence: 79%

Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling

Chowdhury¹,

Zhu

Aloor³

et al. 2015

Molecular & Cellular Proteomics

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“…The data shown in Figure 8.3 and those published by others (Schimanski et al, 2009) suggest a physiological role for ABCA1 in the lactating mammary gland. Furthermore they may suggest that ABCG1 could be more important for processes occurring in mammary secretory cells of lactating rather than nonlactating mammary tissue.…”

supporting

confidence: 70%

“…ABCA1 and ABCA3 expression was identified by immunohistochemistry in the epithelium of normal as well as in neoplastic human breast tissues, but also in breast cancer cell lines (Schimanski et al, 2009). It was reported that ABCA3 and ABCA1 were highly expressed in normal mammary gland epithelium.…”

Section: Protein Localization Of Cholesterol Transportersmentioning

confidence: 99%

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Cholesterol transporters in lactating and nonlactating human mammary tissue

Albrecht¹,

Huang²,

Ontsouka³

2013

Handbook of Dietary and Nutritional Aspects of Human Breast Milk

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In mammals milk is the principal nutrient for neonates at birth. The basic milk composition is similar between different mammals, but the content of individual constituents such as lipids may differ significantly from one species to another. The milk fat fraction is mainly composed of triglycerides which account for more than 95% of the lipids found in human and bovine milk. Though sterols and in particular cholesterol, the predominant milk sterol, represent less than 0.5% of the total milk lipid fraction, they are of ultimate importance for biological processes such as the formation of biological membranes or as precursors for steroid hormone synthesis. Cholesterol found in milk originates either from blood uptake or from local synthesis. This chapter provides an overview of cholesterol exchanges between the blood, the mammary tissue and the milk. The current knowledge on the expression, localization and function of candidate cholesterol transporters in mammary tissues of human, murine and bovine origin is summarized. Different mechanisms of how cholesterol can be transferred via the mammary tissue into milk, and which active cholesterol transporters are likely to play a role in this process will be discussed.Keywords: cholesterol transport, milk composition, ABC transporter, mammary gland 148Handbook of dietary and nutritional aspects of human breast milk C. Albrecht, X. Huang and E.C. Ontsouka Key facts• Cholesterol is a crucial molecule which, as a cell membrane constituent, is essential for cell growth and renewal as well as for the synthesis of specific hormones.• Milk and its derived products are one of the most important sources of cholesterol in the human diet (both adults and infants). Regarding its role as a nutrient found in milk considerable and often controversial effects of cholesterol on human health are discussed. In this context it seems important to distinguish cholesterol effects in babies/infants as opposed to adults.• Babies consume very high amounts of cholesterol per kg of body weight compared to adults without showing detrimental effects attributed to high cholesterol intake. Interestingly, the increase of serum cholesterol levels in breastfed babies is more pronounced as compared to milk formula fed babies.• The identification of active cholesterol transporters in other peripheral tissues have revolutionized the current thinking of how cholesterol is transported or exported from epithelial cells. Therefore, the current concept of cholesterol trafficking in the mammary gland needs re-thinking and the role of active cholesterol transporters in this process has to be elucidated. Summary points• Cholesterol is the predominant sterol found in milk. It enters the latter from the blood where it circulates bound to various carrier proteins such as very low density lipoprotein, low density lipoprotein, and high density lipoprotein.• The transcellular transport of cholesterol in the mammary gland implies an uptake from the blood circulation, redistribution in cytosolic compartments and re...

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“…ABCA3 expression in lung cancer appears to be closely associated with adenoid differentiation, an observation recently also made in breast cancer. In mammary cancer tissue, the level of ABCA3 expression correlated with the degree of glandular differentiation, and lower levels of ABCA3 expression were associated with a more aggressive phenotype of the tumor cells [29]. This appears similar to the situation in lung cancer with low expression levels of ABCA3 in SCLC, the most aggressive variant of the disease.…”

Section: Discussionmentioning

confidence: 87%

Intracellular ATP-Binding Cassette Transporter A3 is Expressed in Lung Cancer Cells and Modulates Susceptibility to Cisplatin and Paclitaxel

Overbeck

Hupfeld²,

Krause³

et al. 2013

Oncology

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Patients with advanced-stage bronchial cancer benefit from systemic cytostatic therapy, in particular from regimens integrating cisplatin and taxanes. However, eventual disease progression leads to a fatal outcome in most cases, originating from tumor cells resisting chemotherapy. We here show that the intracellular ATP-binding cassette transporter A3 (ABCA3), previously recognized as critical for the secretion of surfactant components from type 2 pneumocytes, is expressed in non-small-cell lung cancer (NSCLC) cells. With some heterogeneity in a given specimen, expression levels detected immunohistochemically in primary cancer tissue were highest in adenocarcinomas and lowest in small cell lung cancers. Genetic silencing of ABCA3 in the NSCLC cell line models A549, NCI-H1650 and NCI-H1975 significantly increased tumor cell susceptibility to the cytostatic effects of both cisplatin (in all cell lines) and paclitaxel (in two of three cell lines). Taken together, ABCA3 emerges as a modulator of NSCLC cell susceptibility to cytostatic therapy.

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Expression of the Lipid Transporters ABCA3 and ABCA1 is Diminished in Human Breast Cancer Tissue

Cited by 61 publications

References 19 publications

Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling

Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling

Cholesterol transporters in lactating and nonlactating human mammary tissue

Intracellular ATP-Binding Cassette Transporter A3 is Expressed in Lung Cancer Cells and Modulates Susceptibility to Cisplatin and Paclitaxel

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