Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.

Objectives-Previous studies indicated that oral estrogen increased C-reactive protein by a first-pass hepatic effect. In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women. Methods and Results-In 29 postmenopausal women without coronary heart disease, we conducted a randomized crossover placebo-controlled study to compare effects of transdermal versus oral estrogen on SAA and HDL-SAA. SAA, apolipoprotein A-I, HDL, and HDL-SAA were measured before and after 8 weeks of transdermal estradiol (100 g per day), oral-conjugated estrogens (0.625 mg per day), or placebo. We found that oral estrogen significantly increased levels of SAA, HDL, and HDL-SAA, whereas transdermal estrogen reduced both SAA and HDL-SAA but had no effect on HDL in the same women. Conclusions-Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the route of administration may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes. Key Words: hormones Ⅲ inflammation Ⅲ serum amyloid A Ⅲ menopause Ⅲ HDL T he role of inflammation in the development of atherosclerosis is firmly established. Among markers of systemic inflammation, C-reactive protein (CRP) is one of the most important acute-phase proteins known to be independent predictors of adverse cardiovascular events in otherwise healthy women. 1 Recent studies by our group and others indicated that oral estrogen replacement therapy (ERT) caused a sustained increase in CRP, which may explain the increased risks of cardiovascular events of ERT in clinical trials. 2,3 This increase in CRP was avoided by transdermal estrogen, implicating a first-pass hepatic effect. See page 1741Serum amyloid A (SAA) is another acute-phase protein that determines long-term cardiovascular prognosis in women. 1 Like CRP, SAA is produced by the liver and has been shown to directly promote atherosclerosis and vascular inflammation. 4 However, unlike CRP, SAA can form a complex with high-density lipoprotein (HDL) in the plasma, and the elevated SAA content of the HDL particle (HDL-SAA) has been shown to interfere with antiatherogenic, antioxidative, and anti-inflammatory HDL function. 5 Although the influence of estrogen on CRP has been studied extensively, effects of estrogen administration on SAA are still unknown. The purpose of our present study is not only to determine whether the route of estrogen administration influences SAA levels but also HDL-SAA in postmenopausal women. MethodsThe study was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas. After informed written consent was obtai...