Reduction of breast lymphoedema secondary to breast cancer: a randomised controlled exercise trial.

BACKGROUND: Breast lymphoedema can occur following surgical treatment for breast cancer. We investigated whether an exercise program reduced breast lymphoedema symptoms compared to a non-exercise control group. METHODS: A single-blinded randomised controlled trial was conducted in which women with stable breast lymphoedema (n = 89) were randomised into an exercise (n = 41) or control (n = 47) group. The intervention comprised a 12-week combined aerobic and resistance training program, supervised weekly by an accredited exercise physiologist. All participants completed a weekly symptoms diary and were assessed monthly to ensure that there was no exacerbation of their lymphoedema. Changes in the breast were captured physically with ultrasound and bioimpedance spectroscopy and changes in symptoms were captured using European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer (BR23) and Lymphoedema Symptom Intensity and Distress questionnaires. RESULTS: The exercise group reported a greater reduction in breast-related symptoms than the control group, assessed by the EORTC BR23 breast symptom questions. Measures of extracellular fluid, assessed with bioimpedance spectroscopy ratio, decreased in the exercise group compared to the control group. No significant difference was detected in dermal thickness in the breast, assessed by ultrasound. Session attendance in the exercise sessions was high, with two musculoskeletal adverse events reported, but no exacerbations of lymphoedema observed. CONCLUSION: Combined resistance and aerobic exercise training is safe for women living with breast lymphoedema. Preliminary data suggest exercise training can reduce breast lymphoedema symptoms to a greater extent than usual care.

Aromatase expression in atypical ductal hyperplasia in women.

PURPOSE: To determine the levels of aromatase in atypical ductal hyperplasia (ADH) lesions, tissue surrounding the ADH, and in dense and non-dense normal breast tissue. We postulated that excess aromatase in breast tissue might, through production of increased estrogen, drive the carcinogenic process. Estrogens and their metabolites are thought to contribute to the development of breast cancer through estrogen receptor-mediated mechanisms and genotoxic effects of estrogen metabolites. ADH is a benign lesion of the breast which is associated with substantially increased risk for subsequent development of breast cancer. After 25 years, approximately 30% of women with ADH develop breast cancer. In women with three or more separate ADH lesions at the same time, 47% will develop breast cancer over that time period. Another important risk factor for breast cancer is the presence of mammographically dense breast tissue. METHODS: We utilized quantitative immunochemical analysis of aromatase in biopsy tissue to test this possibility. Previously published results comparing dense with non-dense breast tissue in normal women (Vachon et al. Breast Cancer Res Treat 125:243-252, 2011) were used for comparisons with ADH. A well-characterized histochemical H-score was employed for quantitative assessment of aromatase in the various tissue studied. RESULTS: The H-score of aromatase staining was statistically significantly higher (p = 0.003) in the ADH epithelium than surrounding epithelial tissue. In order of H-score from highest to lowest were ADH, issue surrounding ADH, dense normal and non-dense normal breast tissues. The levels of aromatase in a subset of women with ADH who went on to develop breast cancer were not higher than in women who did not. CONCLUSIONS: We suggest from these studies that overexpression of aromatase in breast tissue and its resultant increase in estradiol levels may contribute to the later development of breast cancer in women with ADH.

The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells.

In this study, we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces stabilization and accumulation of Aurora-A mitotic kinase that ultimately drives the transition from an epithelial to a highly invasive mesenchymal phenotype in estrogen receptor α-positive (ERα(+)) breast cancer cells. The transition from an epithelial- to a mesenchymal-like phenotype was characterized by reduced expression of ERα, HER-2/Neu overexpression and loss of CD24 surface receptor (CD24(-/low)). Importantly, expression of key epithelial-to-mesenchymal transition (EMT) markers and upregulation of the stemness gene SOX2 was linked to acquisition of stem cell-like properties such as the ability to form mammospheres in vitro and tumor self-renewal in vivo. Moreover, aberrant Aurora-A kinase activity induced phosphorylation and nuclear translocation of SMAD5, indicating a novel interplay between Aurora-A and SMAD5 signaling pathways in the development of EMT, stemness and ultimately tumor progression. Importantly, pharmacological and molecular inhibition of Aurora-A kinase activity restored a CD24(+) epithelial phenotype that was coupled to ERα expression, downregulation of HER-2/Neu, inhibition of EMT and impaired self-renewal ability, resulting in the suppression of distant metastases. Taken together, our findings show for the first time the causal role of Aurora-A kinase in the activation of EMT pathway responsible for the development of distant metastases in ERα(+) breast cancer cells. Moreover, this study has important translational implications because it highlights the mitotic kinase Aurora-A as a novel promising therapeutic target to selectively eliminate highly invasive cancer cells and improve the disease-free and overall survival of ERα(+) breast cancer patients resistant to conventional endocrine therapy.

Nitric oxide inhibits peroxide-mediated endothelial toxicity.

BACKGROUND: Oxidant molecules and nitric oxide (NO) have each been implicated as mediators of endothelial cell damage, but the biologic effect of these molecules acting in concert is incompletely understood. MATERIALS AND METHODS: We studied the effects of an NO donor, S-nitroso-acetyl-D,L-penicillamine (SNAP), in combination with the peroxidants tert-butyl hydroperoxide (TBH) and hydrogen peroxide (H2O2) on rabbit aortic endothelial cells in culture. Cell viability was assessed using Alamar blue, a nontoxic dye indicator of cell metabolism. Lipid peroxidation was assessed using a chemiluminescent single-photon counting technique. RESULTS: After 90 min exposure to test reagents, there was concentration-dependent cytotoxicity for both TBH and H2O2. Peroxidant-induced cytotoxicity was significantly ameliorated by SNAP (10(-4)-10(-3)M). N-Acetylpenicillamine and NO-depleted SNAP failed to demonstrate a cytoprotective effect against peroxidant cellular injury, thus implicating NO as the agent responsible for the protective effect. SNAP reduced lipid peroxidation caused by 10(-3) M TBH in a dose-dependent manner. Preincubation of cells with SNAP before exposure to peroxidants alone had no effect on toxicity. CONCLUSIONS: NO is cytoprotective to the endothelium in the presence of peroxidants through a reduction of lipid peroxidation.

Nitric oxide and the pulmonary artery smooth muscle cell.

Nitric oxide (NO) is produced by the enzyme nitric oxide synthase (NOS), which exists in different isoforms in various tissues. The inducible NOS (iNOS) isoform of the enzyme is expressed in vascular smooth muscle in response to lipopolysaccharide and inflammatory mediators. When this expression of iNOS occurs in the lung, the NO produced may play a role in the inflammatory process of acute lung injury. This article reviews the research that characterizes iNOS in rat pulmonary artery smooth muscle and discusses current investigation into the role of NO in sepsis and injury.