Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-α activation via the mitogen-activated protein kinase pathway

INTRODUCTION: Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. METHODS: Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17β-estradiol and progesterone. The 17β-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. RESULTS: IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17β-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the α-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-α in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D(1 )and transforming growth factor-β(3 )in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous rats. CONCLUSION: We argue that tumor initiation (transformation and fixation of mutations) may be similar in parous and age-matched virgin animals, suggesting that the main differences in tumor formation lie in differences in tumor progression caused by the altered hormonal environment associated with parity. Furthermore, we provide evidence supporting the notion that tumor growth promotion seen in IGF-I-treated parous rats is caused by activation of estrogen receptor-α via the Raf/Ras/mitogen-activated protein kinase cascade

Concurrent sexual partnerships and associated factors: a cross-sectional population-based survey in a rural community in Africa with a generalised HIV epidemic.

BACKGROUND: Although concurrent sexual partnerships may play an important role in HIV transmission in Africa, the lack of an agreed definition of concurrency and of standard methodological approaches has hindered studies. In a long-standing general population cohort in rural Uganda we assessed the prevalence of concurrency and investigated its association with sociodemographic and behavioural factors and with HIV prevalence, using the new recommended standard definition and methodological approaches. METHODS: As part of the 2010 annual cohort HIV serosurvey among adults, we used a structured questionnaire to collect information on sociodemographic and behavioural factors and to measure standard indicators of concurrency using the recommended method of obtaining sexual-partner histories. We used logistic regression to build a multivariable model of factors independently associated with concurrency. RESULTS: Among those eligible, 3,291 (66%) males and 4,052 (72%) females participated in the survey. Among currently married participants, 11% of men and 25% of women reported being in a polygynous union. Among those with a sexual partner in the past year, the proportion reporting at least one concurrent partnership was 17% in males and 0.5% in females. Polygyny accounted for a third of concurrency in men and was not associated with increased HIV risk. Among men there was no evidence of an association between concurrency and HIV prevalence (but too few women reported concurrency to assess this after adjusting for confounding). Regarding sociodemographic factors associated with concurrency, females were significantly more likely to be younger, unmarried, and of lower socioeconomic status than males. Behavioural factors associated with concurrency were young age at first sex, increasing lifetime partners, and a casual partner in the past year (among men and women) and problem drinking (only men). CONCLUSIONS: Our findings based on the new standard definition and methodological approaches provide a baseline for measuring changes in concurrency and HIV incidence in future surveys, and a benchmark for other studies. As campaigns are now widely conducted against concurrency, such surveys and studies are important in evaluating their effectiveness in decreasing HIV transmission