Proteasomes are the primary degradation machinery for oxidatively damaged proteins that compose a class of misfolded protein substrates. Cellular levels of reactive oxygen species increase with age and this cellular propensity is particularly harmful when combined with the age-associated development of various human disorders including cancer, neurodegenerative disease and muscle atrophy. Proteasome activity is reportedly downregulated in these disease conditions. Herein, we report that docosahexaenoic acid (DHA), a major dietary omega-3 polyunsaturated fatty acid, mediates intermolecular protein cross-linkages through oxidation, and the resulting protein aggregates potently reduce proteasomal activity both in vitro and in cultured cells. Cellular models overexpressing aggregation-prone proteins such as tau showed significantly elevated levels of tau aggregates and total ubiquitin conjugates in the presence of DHA, thereby reflecting suppressed proteasome activity. Strong synergetic cytotoxicity was observed when the cells overexpressing tau were simultaneously treated with DHA. Antioxidant N-acetyl cysteine significantly desensitized the cells to DHA-induced oxidative stress. DHA significantly delayed the proteasomal degradation of muscle proteins in a cellular atrophy model. Thus, the results of our study identified DHA as a potent inducer of cellular protein aggregates that inhibit proteasome activity and potentially delay systemic muscle protein degradation in certain pathologic conditions.
Atrophy ; Cells, Cultured ; Cysteine ; Humans ; In Vitro Techniques* ; Muscle Fibers, Skeletal* ; Muscle Proteins ; Muscular Atrophy* ; Neurodegenerative Diseases ; Oxidative Stress ; Proteasome Endopeptidase Complex* ; Protein Aggregates* ; Reactive Oxygen Species ; Ubiquitin

PURPOSE: A case-control study was conducted to evaluate the association between diet and breast cancer in Korean women. METHODS: The eligible subjects consisted of a series of histologically confirmed incident breast cancer patients (n= 1063) and non-cancer controls (n=1002) admitted to the departments of surgery at four teaching hospitals located in Seoul, Korea (Seoul National University Hospital, Borame Hospital, Samsung Medical Canter, and Asan medical Center) between 1995 and 2002, from whom blood samples were available. After excluding subjects with a previous history of cancer, hysterectomy or oophorectomy, the final study population consisted of 819 cases and 713 controls. The demographic characteristics and other information were collected by interviewed questionnaire. Dietary information obtained by trained interviewer using food frequency questionnaires. RESULTS: Women educated more than 12 years (OR=1.9, 95% CI: 1.4~2.7), with a higher body mass index (BMI) (OR= 1.4, 95% CI: 1.1~2.0) and a positive family history of breast cancer among the first degree relatives (OR=2.5, 95% CI: 1.3~4.3) were significant risk factors for breast cancer. The longer the exposure to estrogen during their lifetime, the higher the observed risk of breast cancer was (p for trend<0.001). The risk for breast cancer was increased with frequent consumption of cereals (OR=1.8, 95% CI: 1.8~2.5), potatoes (OR=1.8, 95% CI: 1.4~2.5), nuts and seeds (OR=1.9, 95% CI: 1.1~3.4), mushrooms (OR=1.5, 95% CI: 1.2~1.8), meats (OR=1.5, 95% CI: 1.2~1.9), eggs (OR=1.6, 95% CI: 1.1~2.3) and fish (OR=1.5, 95% CI: 1.2~1.9), whereas the risk decreased with higher intakes of green vegetables (OR=0.6, 95% CI: 0.4~1.0), fruits (OR=0.7, 95% CI: 0.6~0.9) and seaweeds (OR=0.7, 95% CI: 0.5~1.0). CONCLUSION: Certain diets (e.g., high fat, high carbohydrate, low vegetable or fruit intake, etc.) were significantly associated with the risk of breast cancer in Korea women, which were similar to the findings in Western countries.
Agaricales ; Body Mass Index ; Breast Neoplasms* ; Breast* ; Case-Control Studies* ; Edible Grain ; Chungcheongnam-do ; Diet* ; Eggs ; Estrogens ; Female ; Fruit ; Hospitals, Teaching ; Humans ; Hysterectomy ; Korea ; Meat ; Nuts ; Ovariectomy ; Ovum ; Surveys and Questionnaires ; Risk Factors ; Seoul ; Solanum tuberosum ; Vegetables

PURPOSE: To estimate the cumulative risk till each age (penetrance) of breast and ovarian cancers among female family members with BRCA1 and BRCA2 mutation. METHODS: Among the 61 BRCA1 mutation carriers in the 42 families and 47 BRCA2 mutation carriers in 31 families identified at 5 academic breast clinics, the probands were excluded to estimate the cumulative risk till each age of breast cancer in the Korean BRCA1 and BRCA2 carriers. Using Kaplan-Meier analyses, cumulative cancer risk estimates were determined. RESULTS: By the age 70, the female breast cancer risk for the BRCA1 and BRCA2 mutation carriers was 72.1% (95% confidence interval [CI]=59.5% to 84.8%) and 66.3% (95% CI=41.2% to 91.5%), respectively, and the ovarian cancer risk was 24.6% (95% CI=0% to 50.3%) and 11.1% (95% CI=0% to 31.6%), respectively. The contralateral breast cancer risk at 5 years after primary breast cancer was estimated as 16.2% (95% CI=9.3% to 23.1%) for the 52 breast cancer patients with the BRCA1 mutation and 17.3% (95% CI=9.7% to 24.0%) for the 35 breast cancer patients with the BRCA2 mutation. CONCLUSION: The penetrance of BRCA mutations in Korea is largely consistent with the previous studies on Western populations. However, the small number of the cases, the high proportions of probands in the study subjects, the short term follow-up, and large confidence intervals are the limitations of the current study. The Korean Hereditary Breast Cancer Study (KOHBRA Study) may definitely answer this question.
Breast ; Breast Neoplasms ; Female ; Follow-Up Studies ; Humans ; Korea ; Ovarian Neoplasms ; Penetrance