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PANTHER (Protein Analysis THrough Evolutionary Relationships, http://pantherdb.org) is a widely used online resource for comprehensive protein evolutionary and functional classification, and includes tools for large-scale biological data analysis. Recent development has been focused in three main areas: genome coverage, functional information ('annotation') coverage and accuracy, and improved genomic data analysis tools. The latest version of PANTHER, 10.0, includes almost 5000 new protein families (for a total of over 12 000 families), each with a reference phylogenetic tree including protein-coding genes from 104 fully sequenced genomes spanning all kingdoms of life. Phylogenetic trees now include inference of horizontal transfer events in addition to speciation and gene duplication events. Functional annotations are regularly updated using the models generated by the Gene Ontology Phylogenetic Annotation Project. For the data analysis tools, PANTHER has expanded the number of different 'functional annotation sets' available for functional enrichment testing, allowing analyses to access all Gene Ontology annotations--updated monthly from the Gene Ontology database--in addition to the annotations that have been inferred through evolutionary relationships. The Prowler (data browser) has been updated to enable users to more efficiently browse the entire database, and to create custom gene lists using the multiple axes of classification in PANTHER., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined., Methods: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis., Results: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97-1.71; OR>0-<7 g/day referent = 1.36; 95% CI, 1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index., Conclusions: In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer., Impact: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer., (©2014 American Association for Cancer Research.)

Background: The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors., Methods: In the Male Breast Cancer Pooling Project, a consortium of 11 case-control and 10 cohort investigations involving 2405 case patients (n = 1190 from case-control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design-specific (case-control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided., Results: Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86)., Conclusions: Consistent findings across case-control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones.

Hormone-related cancers account for almost 30% of all cancer cases in the United States. Data from animal experiments and from epidemiological and endocrinological studies in humans support the hypothesis that the individual hormones which control normal growth of target organs can also create the proper conditions for neoplastic transformation. The concept that hormones can cause, i.e., increase the incidence of, human cancer is most developed for the four hormone-related cancers which are numerically the most important, namely, breast, prostate, endometrium, and ovary. Even for these sites, large gaps remain in our knowledge of the responsible hormones and the conditions which create the optimal opportunity for carcinogenesis. Although scanty, the available epidemiological evidence also suggests a hormonal role in the pathogenesis of testis cancer, thyroid cancer, and osteosarcoma. We believe that the primary prevention of all these cancers will probably depend on modification of the factors which affect the secretion and metabolism of the responsible hormones rather than on control of exposure to classical exogenous initiators.

For most cancer sites there is a linear log-log relationship between incidence and age. This relationship does not hold for breast cancer, and certain 'key' breast cancer risk factors suggest that breast tissue does not 'age' in step with calendar time. A quantitative description of 'breast tissue age' is suggested which brings the age-incidence curve of breast cancer into line with the common log-log cancers and explains quantitatively the known key risk factors. The model also explains the 'anomalous' finding that although early first birth is protective, late first birth carries a higher risk than nulliparity. US breast cancer rates are some four to six times the rates in Japan--the model suggests that the key risk factors, when considered jointly with weight, can explain about 85% of the difference.

A case-control study was conducted in Los Angeles County, California, of 163 very young breast-cancer cases (all aged 32 or less at diagnosis) to investigate the role, if any, of oral contraceptives (OC) in the development of the disease. OC use before first full-term pregnancy (FFTP) was associated with an elevated risk, which increased with duration of OC use (relative risk approximately 2.2 at 6 years of use, P < 0.01). This increased risk could not be explained by other risk factors. OC use after FFTP was not associated with any change in risk. A first-trimester abortion before FFTP, whether spontaneous or induced, was associated with a 2.4-fold increase in breast-cancer risk (P < 0.005).

Risk factors for pathologically confirmed uterine leiomyomas (fibroids) were investigated using data from the Oxford Family Planning Association study, a long term follow up study of women using various methods of contraception. For each of 535 women who had had a fibroid an individual control was selected who matched the patient on age, date of entry into the cohort, and family planning clinic at recruitment and who was alive (and still being followed up) at the date the patient underwent surgery for fibroids. Case-control analysis showed that reproductive experiences were closely linked to development of fibroids. Risk of fibroids decreased consistently with increasing number of term pregnancies; women with five term pregnancies had only a quarter of the risk of women who had had none. Risk also decreased consistently with increasing duration of oral contraceptive use; the risk of fibroids was reduced by some 31% in women who had used oral contraceptives for 10 years. Risk was strongly related to weight: women who weighed under 55 kg had a particularly low risk, and overall the risk rose roughly 21% for each 10 kg increase. Cigarette smoking was associated with a decreased risk of fibroids; smokers of 20 cigarettes a day had a risk roughly two thirds that of non-smokers. These risk factors have all previously been identified as risk factors for endometrial cancer; this strongly suggests that the underlying risk factor is "unopposed" oestrogen.

A case-control study was conducted in Los Angeles County, CA, of 75 male breast cancer cases aged 20-74 yr at diagnosis to investigate the role of a number of suspected risk factors. The study involved both interviews and laboratory measurements. Factors under study included fertility and marital history, obesity, alcohol and cigarette consumption, use of drugs known or suspected of causing gynecomastia, family history of breast cancer, history of radiation exposure to the upper body, sex chromatin analysis, serum levels of prolactin, testosterone, estrone, estradiol and sex-hormone-binding globulin, as well as urinary levels of estrone, estradiol, and estriol. Two patients versus no controls tested positive for sex chromatin and were excluded from further analyses. The only statistically significant risk factor identified was greater weight of the cases at age 30; a man who weighed 80 or more kg at age 30 had twice the risk of breast cancer of a man weighing less than 60 kg at that age. Serum estrone levels were positively, and sex-hormone-binding globulin levels were negatively, related to body weight, and we interpret the greater weight of the cases as suggesting that the underlying risk factor is an increased exposure to bioavailable estrogen. None of the differences observed between cases and controls for either the serum or urinary hormone levels was, however, statistically significant and there did not appear to be any large absolute excess of estrogens or deficit of testosterone in the cases. This apparent contradiction may be explained by the fact that there was little difference in weight between the cases and controls at the time of sampling.

A case-control study was conducted in Los Angeles County, California, of 127 endometrial cancer cases aged 45 years or less at diagnosis, to investigate the role of fertility, obesity and exogenous oestrogens in the development of the disease in young women. Use of sequential oral contraceptive (SOCs) or oestrogen replacement therapy (ERT) for greater than or equal to 2 years was strongly associated with increased risk of endometrial cancer. After excluding these cases, since the SOC or ERT use was probably the cause of their disease, we were left with 110 case-control pairs for further study. Among these remaining case-control pairs increasing parity was strongly associated with decreased risk (relative risk of 0.12 for women of parity 3 compared to nulliparous women, P less than 0.001). Current weight was associated with increased risk (relative risk of 17.7 for women weighing greater than or equal to 190 lbs compared to women weighing less than 130 lbs, P less than 0.001). Combination oral contraceptive (COC) use was associated with a decreased risk, which decreased with duration of COC use (relative risk of approximately 0.28 at 5 years of use, P less than 0.001), but the estimate of the protective effect was reduced and became statistically non-significant when allowance was made for weight and parity. The protective effect of COC use was only clearly evident in women who had less than 3 live-births and weighed less than 170 lbs. These results provide further support for the "unopposed" oestrogen hypothesis of the aetiology of endometrial cancer.

Higher lung cancer mortality rates occurred in males living in certain heavily industrialized areas of Los Angeles County, California. These areas were characterized by elevated concentrations of benzo[a]pyrene and other polynuclear aromatic hydrocarbons of primarily industrial origin in the soil and air.