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

Regulation of protein transport from the Golgi complex to the endoplasmic reticulum by CDC42 and N-WASP.

Actin is involved in the organization of the Golgi complex and Golgi-to-ER protein transport in mammalian cells. Little, however, is known about the regulation of the Golgi-associated actin cytoskeleton. We provide evidence that Cdc42, a small GTPase that regulates actin dynamics, controls Golgi-to-ER protein transport. We located GFP-Cdc42 in the lateral portions of Golgi cisternae and in COPI-coated and noncoated Golgi-associated transport intermediates. Overexpression of Cdc42 and its activated form Cdc42V12 inhibited the retrograde transport of Shiga toxin from the Golgi complex to the ER, the redistribution of the KDEL receptor, and the ER accumulation of Golgi-resident proteins induced by the active GTP-bound mutant of Sar1 (Sar1[H79G]). Coexpression of wild-type or activated Cdc42 and N-WASP also inhibited Golgito-ER transport, but this was not the case in cells expressing Cdc42V12 and N-WASP(AWA), a mutant form of N-WASP that lacks Arp2/3 binding. Furthermore, Cdc42V12 recruited GFP-NWASP to the Golgi complex. We therefore conclude that Cdc42 regulates Golgi-to-ER protein transport in an N-WASP¿dependent manner

Dyslipidemia and chronic inflammation markers are correlated with telomere length shortening in Cushing's syndrome

INTRODUCTION: Cushing's syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging. - AIM: to evaluate relationships between TL, CVR and inflammation markers in CS. - METHODS: in a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking-matched controls were included. Total white blood cell TL was measured by TRF-Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL. - RESULTS: dyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328±1274 vs 7957±1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187±1309 vs 7868±1104; active: 7203±1262 vs 8615±1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r-0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and -0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956±1280 vs 7860±1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL. -CONCLUSION :TL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a "low" grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS

Telomere length analysis in Cushing's syndrome

Introduction: Hypercortisolism in Cushing's syndrome (CS) is associated with increased morbidity and mortality. Hypercortisolism also occurs in chronic depressive disorders and stress, where telomere length (TL) is shorter than in controls. We hypothesized that shortening of telomere might occur in CS and contribute to premature aging and morbidity. - Aim: To investigate TL in CS patients compared with controls. - Methods: Seventy-seven CS patients (14 males, 59 pituitary, 17 adrenal, and one ectopic; 21 with active disease) were compared with 77 gender-, age-, and smoking-matched controls. Fifteen CS were evaluated longitudinally, during active disease and after remission of hypercortisolism. Leukocyte TL was measured by telomere restriction fragment-Southern technique. Clinical markers were included in a multiple linear regression analysis to investigate potential predictors of TL. - Results : Mean TL in CS patients and controls was similar (7667 vs 7483 bp, NS). After adjustment for age, in the longitudinal evaluation, TL was shorter in active disease than after remission (7273 vs 7870, P<0.05). Age and dyslipidemia were negative predictors (P<0.05), and total leukocyte count was a positive predictor for TL (P<0.05). As expected, a negative correlation was found between TL and age (CS, R=−0.400 and controls, R=−0.292; P<0.05). No correlation was found between circulating cortisol, duration of exposure to hypercortisolism or biochemical cure and TL. - Conclusion : Even though in the cross-sectional comparison of CS and controls no difference in TL was found, in the longitudinal evaluation, patients with active CS had shorter TL than after biochemical cure of hypercortisolism. These preliminary results suggest that hypercortisolism might negatively impact telomere maintenance. Larger studies are needed to confirm these findings

N-Ras induces alterations in Golgi complex architecture and in constitutive protein transport

Aberrant glycosylation of proteins and lipids is a common feature of many tumor cell types, and is often accompanied by alterations in membrane traffic and an anomalous localization of Golgi-resident proteins and glycans. These observations suggest that the Golgi complex is a key organelle for at least some of the functional changes associated with malignant transformation. To gain insight into this possibility, we have analyzed changes in the structure and function of the Golgi complex induced by the conditional expression of the transforming N-Ras(K61) mutant in the NRK cell line. A remarkable and specific effect associated with this N-Ras-induced transformation was a conspicuous rearrangement of the Golgi complex into a collapsed morphology, Ultrastructural and stereological analyses demonstrated that the Golgi complex was extensively fragmented. The collapse of the Golgi complex was also accompanied by a disruption of the actin cytoskeleton, Functionally, N-Ras-transformed KT8 cells showed an increase in the constitutive protein transport from the trans-Golgi network to the cell surface, and did not induce the appearance of aberrant cell surface glycans, The Golgi complex collapse, the actin disassembly, and the increased constitutive secretion were all partially inhibited by the phospholipase A(2) inhibitor 4-bromophenylacyl bromide. The results thus suggest the involvement of the actin cytoskeleton in the shape of the Golgi complex, and intracellular phospholipase A(2) in its architecture and secretory function

Regulation of protein transport from the Golgi complex to the endoplasmic reticulum by CDC42 and N-WASP.

Actin is involved in the organization of the Golgi complex and Golgi-to-ER protein transport in mammalian cells. Little, however, is known about the regulation of the Golgi-associated actin cytoskeleton. We provide evidence that Cdc42, a small GTPase that regulates actin dynamics, controls Golgi-to-ER protein transport. We located GFP-Cdc42 in the lateral portions of Golgi cisternae and in COPI-coated and noncoated Golgi-associated transport intermediates. Overexpression of Cdc42 and its activated form Cdc42V12 inhibited the retrograde transport of Shiga toxin from the Golgi complex to the ER, the redistribution of the KDEL receptor, and the ER accumulation of Golgi-resident proteins induced by the active GTP-bound mutant of Sar1 (Sar1[H79G]). Coexpression of wild-type or activated Cdc42 and N-WASP also inhibited Golgito-ER transport, but this was not the case in cells expressing Cdc42V12 and N-WASP(AWA), a mutant form of N-WASP that lacks Arp2/3 binding. Furthermore, Cdc42V12 recruited GFP-NWASP to the Golgi complex. We therefore conclude that Cdc42 regulates Golgi-to-ER protein transport in an N-WASP¿dependent manner

Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes

Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause-effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF-1 system

LDL, HDL and endocrine-related cancer : From pathogenic mechanisms to therapies

Cholesterol is essential for a variety of functions in endocrine-related cells, including hormone and steroid production. We have reviewed the progress to date in research on the role of the main cholesterol-containing lipoproteins; low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and their impact on intracellular cholesterol homeostasis and carcinogenic pathways in endocrine-related cancers. Neither LDL-cholesterol (LDL-C) nor HDL-cholesterol (HDL-C) was consistently associated with endocrine-related cancer risk. However, preclinical studies showed that LDL receptor plays a critical role in endocrine-related tumor cells, mainly by enhancing circulating LDL-C uptake and modulating tumorigenic signaling pathways. Although scavenger receptor type BI-mediated uptake of HDL could enhance cell proliferation in breast, prostate, and ovarian cancer, these effects may be counteracted by the antioxidant and anti-inflammatory properties of HDL. Moreover, 27-hydroxycholesterol a metabolite of cholesterol promotes tumorigenic processes in breast and epithelial thyroid cancer. Furthermore, statins have been reported to reduce the incidence of breast, prostate, pancreatic, and ovarian cancer in large clinical trials, in part because of their ability to lower cholesterol synthesis. Overall, cholesterol homeostasis deregulation in endocrine-related cancers offers new therapeutic opportunities, but more mechanistic studies are needed to translate the preclinical findings into clinical therapies

Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes

Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause-effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF-1 system