Leptin signaling in breast cancer: an overview

The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.     

Metabolic syndrome and incidence of liver and breast cancers in Japan

Aim of the study To clarify the relationship between the presence of metabolic syndrome and the incidence of cancer in a general Japanese population. Methods A retrospective cohort study was conducted among 8329 male and 15,386 female subjects between 1992 and 2000. The analysis used five definitions of metabolic syndrome. The information on the site-specific cancer was obtained from the population-based cancer registry. A Cox proportional hazard model was adapted for the statistical analyses. The average follow-up period was 9.1 years. Results The National Cholesterol Education Program Adult Treatment Panel III 2001 criteria of metabolic syndrome revealed that the hazard ratio of metabolic syndrome for liver cancer was 1.89 (95% confidence interval (CI) 1.11–3.22) for males, and 3.67 (CI 1.78–7.57) for females. The hazard ratio for female breast cancer was 2.87 (CI 1.67–4.94). When the analysis was limited to postmenopausal women (55 years of age or older), the ratio increased to 6.73 (CI 2.93–15.43). The NCEP-ATPIII 2001 criteria were superior to the other four proposed criteria for predicting the incidence of cancer. In the statistical model, which included all components of the metabolic syndrome and the metabolic syndrome (present or absent), high blood glucose was a significant associated factor for all sites and liver cancers, whereas the metabolic syndrome was found to be a significant associated factor for breast cancer. Conclusion Metabolic syndrome may play an important role in the incidence of breast cancer. High fasting plasma glucose level is considered to be useful as an associated factor for the incidence of all-sites and liver cancer.     

One-carbon metabolism and breast cancer: an epidemiological perspective

One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polymorphisms and supplies of cofactors （e.g. folate, vitamins B） involved in this pathway have been shown to influence cancer risk and even survival. In this review, we summarized the epidemiological evidence for one-carbon metabolism, from both genetics and lifestyle aspects, in relation to breast cancer risk. We also discussed this pathway in relation to breast cancer survival and the modulation of one-carbon polymorphism in chemotherapy. Emerging evidence on modulation of DNA methylation by one-carbon metabolism suggests that disruption of epigenome might have been the underlying mechanism. More results are expected and will be translated to guidance to the general population for disease prevention as well as to clinicians for treatment and management of the disease.     

Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness

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Cryolumpectomy for breast cancer: an experimental study

The effects of cryosurgical procedures and surgical excision in preventing the local recurrence of mammary adenocarcinoma were studied in BALB/cfC3H mice carrying syngeneic, virus-induced mammary adenocarcinomas transplanted into the fourth mammary fat pad. In this report we present evidence demonstrating that cryosurgical procedures involving multiple freeze-thaw cycles followed by tumor excision markedly reduce the local recurrence rate of mouse mammary cancer. Surgical resection without cryotreatment resulted in an 80% local recurrence rate; in contrast, cryotreatment consisting of three freeze-thaw cycles before excision prevented local tumor recurrence in 70% of the animals. The use of cryotherapy and local excision (cryolumpectomy) in the treatment of human breast cancer is discussed.     

Calmodulin: an overview

Calmodulin is a 16,700-dalton Ca2+-binding protein ubiquitous in the eukaryotes. It has no intrinsic enzymatic activity, but it regulates a wide spectrum of enzymes that control many basic cellular processes, ranging from the metabolism of cyclic nucleotides, Ca2+, and glycogen to contractile activity and stimulus-secretion coupling. Mounting evidence now indicates that calmodulin is the major intracellular Ca2+ receptor that remained elusive despite three decades of extensive work by many investigators.     

Hydroxyurea: an overview

Hydroxyurea has been a compound of scientific and clinical interest for over 100 years. A small molecule with many biological properties, hydroxyurea is used in a number of myeloproliferative, neoplastic, and non-hematological diseases. Recently, the agent has been investigated for use in the treatment of Human Immunodeficiency Virus (HIV) disease. Hydroxyurea is associated with dose related bone marrow suppression, crosses the placenta, and is excreted in breast milk. Toxicity is often managed through dose titration. Although adequate attention must be paid to the drug's use in pregnancy and during breast feeding, hydroxyurea's ease of administration, multiplicity of clinical effects, and low cost ensure the drug a place in therapy for years to come.     

Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells

Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC(50)=15 μM. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.     

Hantaviruses: an overview

Hantaviruses are a newly emerging group of rodent-borne viruses that have significant zoonotic potential. Human infection by hantaviruses can result in profound morbidity and mortality, with death rates as high as 50%, and potentially long-term cardiovascular consequences. Hantaviruses are carried by peridomestic and wild rodents worldwide and have occasionally been linked to infections in laboratory rodents. Because these viruses have been associated with significant human disease, they have become the subject of intense scientific investigation. In this review the reader is introduced to the hantaviruses, including hantavirus diseases and their pathogenesis. A review of the biology, morphology, and molecular biology of the hantaviruses with a brief overview of the ecology and biology of hantavirus-rodent pairs is also included. The risks of occupational exposure to hantaviruses, diagnosis of hantavirus infections, and methods for handling potentially infected rodents and tissues are discussed as well.