BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.FWN – Publicaties zonder aanstelling Universiteit Leide

Human somatic cell mutagenesis creates genetically tractable sarcomas

Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further deployed by Sleeping Beauty transposons throughout the genome of human bone explant mesenchymal cells. De novo tumors generated rapidly in this context were high-grade myxofibrosarcomas. Tumor insertion sites were enriched in recurrent somatic copy-number aberration regions from multiple cancer types and could be used to pinpoint new driver genes that sustain somatic alterations in patients. We identified HDLBP, which encodes the RNA-binding protein vigilin, as a candidate tumor suppressor deleted at 2q37.3 in greater than one out of ten tumors across multiple tissues of origin. Hybrid viral-transposon systems may accelerate the functional annotation of cancer genomes by enabling insertional mutagenesis screens in higher eukaryotes that are not amenable to germline transgenesis

Epidemiologia da leishmaniose tegumentar americana e suas relações com a lavoura e o garimpo, em localidade do Estado da Bahia (Brasil) Epidemiology of leishmaniasis related to agriculture and prospecting in a locality of the State of Bahia, Brazil

Realizou-se um estudo sobre a associação entre infecção leishmaniótica e a ocupação dos indivíduos em Lençóis-Bahia (Brasil). Foram utilizados um questionário com variáveis biológicas, sociais e econômicas e o teste de Montenegro. Houve captura de flebotomíneos em locais peri e intra-domiciliares. Encontrou-se maior prevalência da infecção no grupo ocupacional de lavradores/garimpeiros em comparação às demais ocupações. Explica-se esse resultado em razão da dupla exposição dos lavradores/garimpeiros à leishmaniose tegumentar americana, em sua área de moradia e local de trabalho.<br>This study was carried out in the city of Lençóis, State of Bahia, with the objective of verifying the association between leishmaniasis infection and occupation. A Montenegro test and a questionnaire including biological and socio-economic variables were applied to the study group. Sandflies were captured in and around dwellings. The higher-than-average prevalence of leishmaniasis observed among agricultural workers and prospectors is explained by the double exposure to the infection-both at home and at work