The prevalence of Mycobacterium bovis infection in the wild possum population around the perimeter of the Hauhungaroa Ranges, New Zealand, was determined by a cross-sectional study, and risk factors associated with tuberculosis were identified. Of 6083 possums necropsied, 128 (2.1%) showed gross lesions suggestive of tuberculosis infection, and 76 (1.25%) were subsequently confirmed as tuberculous on histopathological examination. Considering only traplines where tuberculosis was detected, adult possums were 1.9 times as likely to be infected as immature animals, and the total prevalence was 5.4% in males compared with 3.9% in females. Adult females were 3.64 times as likely to be infected as immature females, whereas there was no significant age difference for males (odds ratio = 1.46, p=O.29). Immature males were 3.12 times as likely to be infected as immature females. Possums in poor condition were more likely to be found infected than possums in good condition. Tuberculous possums were found in 27 local clusters of infection. The correlation between the prevalence of tuberculosis in possums in zones and the incidence of tuberculosis in cattle on adjoining properties was 0.4 (p
Resistance to androgen receptor (AR) targeting therapeutics in prostate cancer (PC) is a significant clinical problem. Mechanisms by which this is accomplished include AR amplification and expression of AR splice variants, demonstrating that AR remains a key therapeutic target in advanced disease. For the first time we show that IKBKE drives AR signalling in advanced PC. Significant inhibition of AR regulated gene expression was observed upon siRNA-mediated IKBKE depletion or pharmacological inhibition due to inhibited AR gene expression in multiple cell line models including a LNCaP derivative cell line resistant to the anti-androgen, enzalutamide (LNCaP-EnzR). Phenotypically, this resulted in significant inhibition of proliferation, migration and colony forming ability suggesting that targeting IKBKE could circumvent resistance to AR targeting therapies. Indeed, pharmacological inhibition in the CWR22Rv1 xenograft mouse model reduced tumour size and enhanced survival. Critically, this was validated in patient-derived explants where enzymatic inactivation of IKBKE reduced cell proliferation and AR expression. Mechanistically, we provide evidence that IKBKE regulates AR levels via Hippo pathway inhibition to reduce c-MYC levels at cis-regulatory elements within the AR gene. Thus, IKBKE is a therapeutic target in advanced PC suggesting repurposing of clinically tested IKBKE inhibitors could be beneficial to castrate resistant PC patients.
Organochlorines (OC) are a common class of pesticides known as endocrine disruptors in humans. OC pesticides are known to modify the effects of estrogen and testosterone and may act as agonists or antagonists or have mixed effects in the microenvironment of tissues. The pathway to pesticide (xenobiotic) elimination from the body is a multi-step process resulting in excretion of contaminants through the urine or bile. The first step involves oxidation which is primarily carried out by the Phase I enzyme family, cytochrome P450 (CYP), and is typically an activating reaction creating a more polar byproduct. The second step involves conjugation with an endogenous ligand through a Phase II enzyme family, glutathione-S-transferase (GST), and is typically a detoxifying reaction. The goals of this study have been to determine the association between exposure to OC pesticides and risk of a hormone-dependent cancer (breast or prostate) in the Hispanic population of the intensely agricultural San Joaquin Valley of California. Our case-control study involves the use of DNA samples consented from 42 Hispanic female participants and 180 Hispanic male participants and assesses single nucleotide polymorphisms (SNPs) in select xenobiotic-metabolizing genes utilizing three different molecular strategies. For female samples, we found no association between the GSTM1 null polymorphism and breast cancer risk in this sample (O.R. = 0.99, 95% CI=0.28, 3.51), but did find a doubling in breast cancer risk among those women who carried the null polymorphism for GSTT1 (O.R. = 2.21, 95% CI=0.39, 12.63). In females, two CYP1B1 polymorphisms (codon 119 Ala/Ser and codon 432 Val/Leu) were also genotyped. While no association in breast cancer risk for codon 119 (O.R. = 0.77, 95% CI=0.14, 3.70) was found, we did find elevated risk of breast cancer (O.R. 2.33, 95% CI= 0.64, 8.54) at codon 432 (Val>Leu) suggesting that women carrying the Val CYP1B1 allele had higher risk than those women with the Leu/Leu genotype. Due to the small sample population, Odds Ratios are deemed statistically unstable and thus one must be prudent in drawing firm conclusions. Analyses of male samples are ongoing. This study indicates that it is feasible to identify, trace, consent and recruit female and male Hispanic participants in the San Joaquin Valley of California who have recently been diagnosed with breast cancer or prostate cancer for future interventional studies. Citation Format: Yesenia Ibarra, Malika Sahni, Kathryn Patterson, Jessica Borba, Jason A. Bush, Paul K. Mills. Polymorphism analyses in specific xenobiotic-metabolizing genes of Hispanic farmworkers from the San Joaquin Valley with hormone-dependent cancer. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B20. doi:10.1158/1538-7755.DISP13-B20
There is considerable evidence linking cumulative and sustained exposure to estrogens as a key promoter of breast tumor proliferation. Chemicals with estrogenic activity can bind to the estrogen receptor (ER) to affect downstream signaling of estrogen-responsive genes. Organochlorines are a class of chemical pesticides that can act as xenoestrogens to disrupt normal endocrine function. Mitochondria play a significant role in maintenance of energy regulation and cellular detoxification and mitochondrial DNA is sensitive to levels of estrogen. Some members of the Estrogen Related Receptor (ERR) family are known to interact with hypoxia inducible factors to modulate mitochondrial response through the mTOR pathway which is pivotal to cell homeostasis and cellular detoxification. This study investigates the link between two organochlorine pesticides, Methoxychlor and Toxaphene, and the cellular effects by examining the hypothesis that exposure induces differential molecular pathways. Two breast cancer cell lines, MCF-7 (ER+) and MDA-MB-231 (ER-), and a normal breast epithelial cell line MCF-10A are used as a model to evaluate the response to Methoxychlor and Toxaphene treatment. Cytotoxicity studies established different sensitivities of the two breast cancer cell lines to pesticides. MCF-7 was more sensitive to both pesticides, which supports the premise that organochlorines may be acting as endocrine disruptors. Furthermore, pesticide-resistant clones of MCF-7 and MDA-MB-231 were established and compared to their sensitive counterparts. RNA was collected from cells treated in a hypoxic environment, cells treated with a high dose pesticide, and cells that had a co-treatment of hypoxia and pesticide for evaluation of ERR, hypoxic factor expression, and markers of mTOR pathway. Flow cytometry, RT-PCR and immunoblotting demonstrated that treatment affected mitosis and mitochondrial function and we found that ERR and hypoxic factor expression changed in a similar manner suggesting a common mechanism by pesticide treatment or hypoxic conditions. These results provide a basis for understanding specific pesticide-induced molecular mechanisms and their possible relationship to ER+ and ER- mammary epithelial biology. Citation Format: Kathryn Patterson, Julie Hale, Jason Bush. Evaluation of pesticide involvement in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1698. doi:10.1158/1538-7445.AM2013-1698
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