Residential Proximity to Agricultural Pesticide Use and Incidence of Breast Cancer in California, 1988–1997

California is the largest agricultural state in the United States and home to some of the world’s highest breast cancer rates. The objective of our study was to evaluate whether California breast cancer rates were elevated in areas with recent high agricultural pesticide use. We identified population-based invasive breast cancer cases from the California Cancer Registry for 1988–1997. We used California’s pesticide use reporting data to select pesticides for analysis based on use volume, carcinogenic potential, and exposure potential. Using 1990 and 2000 U.S. Census data, we derived age- and race-specific population counts for the time period of interest. We used a geographic information system to aggregate cases, population counts, and pesticide use data for all block groups in the state. To evaluate whether breast cancer rates were related to recent agricultural pesticide use, we computed rate ratios and 95% confidence intervals using Poisson regression models, adjusting for age, race/ethnicity, and neighborhood socioeconomic status and urbanization. This ecologic (aggregative) analysis included 176,302 invasive breast cancer cases and 70,968,598 person-years of observation. The rate ratios did not significantly differ from 1 for any of the selected pesticide categories or individual agents. The results from this study provide no evidence that California women living in areas of recent, high agricultural pesticide use experience higher rates of breast cancer

Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer

BACKGROUND: Signaling pathways that converge on two different transcription factor complexes, NFκB and AP-1, have been identified in estrogen receptor (ER)-positive breast cancers resistant to the antiestrogen, tamoxifen. METHODS: Two cell line models of tamoxifen-resistant ER-positive breast cancer, MCF7/HER2 and BT474, showing increased AP-1 and NFκB DNA-binding and transcriptional activities, were studied to compare tamoxifen effects on NFκB and AP-1 regulated reporter genes relative to tamoxifen-sensitive MCF7 cells. The model cell lines were treated with the IKK inhibitor parthenolide (PA) or the proteasome inhibitor bortezomib (PS341), alone and in combination with tamoxifen. Expression microarray data available from 54 UCSF node-negative ER-positive breast cancer cases with known clinical outcome were used to search for potential genes signifying upregulated NFκB and AP-1 transcriptional activity in association with tamoxifen resistance. The association of these genes with patient outcome was further evaluated using node-negative ER-positive breast cancer cases identified from three other published data sets (Rotterdam, n = 209; Amsterdam, n = 68; Basel, n = 108), each having different patient age and adjuvant tamoxifen treatment characteristics. RESULTS: Doses of parthenolide and bortezomib capable of sensitizing the two endocrine resistant breast cancer models to tamoxifen were capable of suppressing NFκB and AP-1 regulated gene expression in combination with tamoxifen and also increased ER recruitment of the transcriptional co-repressor, NCoR. Transcript profiles from the UCSF breast cancer cases revealed three NFκB and AP-1 upregulated genes – cyclin D1, uPA and VEGF – capable of dichotomizing node-negative ER-positive cases into early and late relapsing subsets despite adjuvant tamoxfien therapy and most prognostic for younger age cases. Across the four independent sets of node-negative ER-positive breast cancer cases (UCSF, Rotterdam, Amsterdam, Basel), high expression of all three NFκB and AP-1 upregulated genes was associated with earliest metastatic relapse. CONCLUSION: Altogether, these findings implicate increased NFκB and AP-1 transcriptional responses with tamoxifen resistant breast cancer and early metastatic relapse, especially in younger patients. These findings also suggest that agents capable of preventing NFκB and AP-1 gene activation may prove useful in restoring the endocrine responsiveness of such high-risk ER-positive breast cancers

Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (Ptrend = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2nd, 3rd, 4th, and 5th quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1st quintile (Ptrend = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (Ptrend = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk. © 2013 Thyagarajan et al

Recent trends in hormone therapy utilization and breast cancer incidence rates in the high incidence population of Marin County, California

<p>Abstract</p> <p>Background</p> <p>Recent declines in invasive breast cancer have been reported in the US, with many studies linking these declines to reductions in the use of combination estrogen/progestin hormone therapy (EPHT). We evaluated the changing use of postmenopausal hormone therapy, mammography screening rates, and the decline in breast cancer incidence specifically for Marin County, California, a population with historically elevated breast cancer incidence rates.</p> <p>Methods</p> <p>The Marin Women's Study (MWS) is a community-based, prospective cohort study launched in 2006 to monitor changes in breast cancer, breast density, and personal and biologic risk factors among women living in Marin County. The MWS enrolled 1,833 women following routine screening mammography between October 2006 and July 2007. Participants completed a self-administered questionnaire that included items regarding historical hormone therapy regimen (estrogen only, progesterone only, EPHT), age of first and last use, total years of use, and reason(s) for stopping, as well as information regarding complementary hormone use. Questionnaire items were analyzed for 1,083 non-Hispanic white participants ages 50 and over. Breast cancer incidence rates were assessed overall and by tumor histology and estrogen receptor (ER) status for the years 1990-2007 using data from the Northern California Surveillance, Epidemiology and End Results (SEER) cancer registry.</p> <p>Results</p> <p>Prevalence of EPHT use among non-Hispanic white women ages 50 and over declined sharply from 21.2% in 1998 to 6.7% by 2006-07. Estrogen only use declined from 26.9% in 1998 to 22.4% by 2006-07. Invasive breast cancer incidence rates declined 33.4% between 2001 and 2004, with drops most pronounced for ER+ cancers. These rate reductions corresponded to declines of about 50 cases per year, consistent with population attributable fraction estimates for EPHT-related breast cancer. Self-reported screening mammography rates did not change during this period. Use of alternative or complementary agents did not differ significantly between ever and never hormone users. Of women who reported stopping EPHT in the past 5 years, 60% cited "health risks" or "news reports" as their primary reasons for quitting.</p> <p>Conclusion</p> <p>A dramatic reduction in EPHT use was followed temporally by a significant reduction in invasive and ER+ breast cancer rates among women living in Marin County, California.</p

Update on HER-2 as a target for cancer therapy: The ERBB2 promoter and its exploitation for cancer treatment

Overexpression of the ERBB2 proto-oncogene is associated with amplification of the gene in breast cancer but increased activity of the promoter also plays a significant role. Members of two transcription factor families (AP-2 and Ets) show increased binding to the promoter in over-expressing cells. Consequently, strategies have been devised to target promoter activity, either through the DNA binding sites for these factors, or through another promoter sequence, a polypurine-polypyrimidine repeat structure. The promoter has also been exploited for its tumour-specific activity to direct the accumulation of cytotoxic compounds selectively within cancer cells. Our current understanding of the ERBB2 promoter is reviewed and the status of these therapeutic avenues is discussed

Sestrin2 Modulates AMPK Subunit Expression and Its Response to Ionizing Radiation in Breast Cancer Cells

Background: The sestrin family of stress-responsive genes (SESN1-3) are suggested to be involved in regulation of metabolism and aging through modulation of the AMPK-mTOR pathway. AMP-activated protein kinase (AMPK) is an effector of the tumour suppressor LKB1, which regulates energy homeostasis, cell polarity, and the cell cycle. SESN1/2 can interact directly with AMPK in response to stress to maintain genomic integrity and suppress tumorigenesis. Ionizing radiation (IR), a widely used cancer therapy, is known to increase sestrin expression, and acutely activate AMPK. However, the regulation of AMPK expression by sestrins in response to IR has not been studied in depth. Methods and Findings: Through immunoprecipitation we observed that SESN2 directly interacted with the AMPKa1b1c1 trimer and its upstream regulator LKB1 in MCF7 breast cancer cells. SESN2 overexpression was achieved using a Flag-tagged SESN2 expression vector or a stably-integrated tetracycline-inducible system, which also increased AMPKa1 and AMPKb1 subunit phosphorylation, and co-localized with phosphorylated AMPKa-Thr127 in the cytoplasm. Furthermore, enhanced SESN2 expression increased protein levels of LKB1 and AMPKa1b1c1, as well as mRNA levels of LKB1, AMPKa1, and AMPKb1. Treatment of MCF7 cells with IR elevated AMPK expression and activity, but this effect was attenuated in the presence of SESN2 siRNA. In addition, elevated SESN2 inhibited IR-induced mTOR signalling and sensitized MCF7 cells to IR through an AMPK-dependent mechanism

Genetic and Cellular Characterization of Caenorhabditis elegans Mutants Abnormal in the Regulation of Many Phase II Enzymes

Background: The phase II detoxification enzymes execute a major protective role against xenobiotics as well as endogenous toxicants. To understand how xenobiotics regulate phase II enzyme expression, acrylamide was selected as a model xenobiotic chemical, as it induces a large number and a variety of phase II enzymes, including numerous glutathione S-transferases (GSTs) in Caenorhabditis elegans. Methodology/Principal Findings: To begin dissecting genetically xenobiotics response pathways (xrep), 24 independent mutants of C. elegans that exhibited abnormal GST expression or regulation against acrylamide were isolated by screening about 3.5610 5 genomes of gst::gfp transgenic strains mutagenized with ethyl methanesulfonate (EMS). Complementation testing assigned the mutants to four different genes, named xrep-1,-2,-3, and-4. One of the genes, xrep-1, encodes WDR-23, a nematode homologue of WD repeat-containing protein WDR23. Loss-of-function mutations in xrep-1 mutants resulted in constitutive expression of many GSTs and other phase II enzymes in the absence of acrylamide, and the wild-type xrep-1 allele carried on a DNA construct successfully cured the mutant phenotype of the constitutive enzyme expression. Conclusions/Significance: Genetic and cellular characterization of xrep-1 mutants suggest that a large number of GSTs and other phase II enzymes induced by acrylamide are under negative regulation by XREP-1 (WDR-23), which is likely to be a functional equivalent of mammalian Keap1 and a regulator of SKN-1, a C. elegans analogue of cap-n-collar Nrf2 (nuclea

Dusty Planetary Systems

Extensive photometric stellar surveys show that many main sequence stars show emission at infrared and longer wavelengths that is in excess of the stellar photosphere; this emission is thought to arise from circumstellar dust. The presence of dust disks is confirmed by spatially resolved imaging at infrared to millimeter wavelengths (tracing the dust thermal emission), and at optical to near infrared wavelengths (tracing the dust scattered light). Because the expected lifetime of these dust particles is much shorter than the age of the stars (>10 Myr), it is inferred that this solid material not primordial, i.e. the remaining from the placental cloud of gas and dust where the star was born, but instead is replenished by dust-producing planetesimals. These planetesimals are analogous to the asteroids, comets and Kuiper Belt objects (KBOs) in our Solar system that produce the interplanetary dust that gives rise to the zodiacal light (tracing the inner component of the Solar system debris disk). The presence of these "debris disks" around stars with a wide range of masses, luminosities, and metallicities, with and without binary companions, is evidence that planetesimal formation is a robust process that can take place under a wide range of conditions. This chapter is divided in two parts. Part I discusses how the study of the Solar system debris disk and the study of debris disks around other stars can help us learn about the formation, evolution and diversity of planetary systems by shedding light on the frequency and timing of planetesimal formation, the location and physical properties of the planetesimals, the presence of long-period planets, and the dynamical and collisional evolution of the system. Part II reviews the physical processes that affect dust particles in the gas-free environment of a debris disk and their effect on the dust particle size and spatial distribution.Comment: 68 pages, 25 figures. To be published in "Solar and Planetary Systems" (P. Kalas and L. French, Eds.), Volume 3 of the series "Planets, Stars and Stellar Systems" (T.D. Oswalt, Editor-in-chief), Springer 201

NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration

BACKGROUND: The influence of the stromal microenvironment on the progression of epithelial cancers has been demonstrated. Unravelling the mechanisms by which stromal cells affect epithelial behaviour will contribute in understanding cellular malignancy. It has been proposed that redox environment has a role in the acquisition of malignancy. In this work, we studied the influence of epithelial cells on the stromal redox status and the consequence of this phenomenon on MCF-7 cell motility. METHODS: We analysed in a co-culture system, the effect of RMF-EG mammary stromal cells on the migratory capacity of MCF-7 cell line. To test whether the NOX-dependent stromal redox environment influences the epithelial migratory behaviour, we knocked down the expression of NOX4 using siRNA strategy. The effect of TGF-b1 on NOX4 expression and activity was analysed by qPCR, and intracellular ROS production was measured by a fluorescent method. RESULTS: Migration of MCF-7 breast epithelial cells was stimulated when co-cultured with RMF-EG cells. This effect depends on stromal NOX4 expression that, in turn, is enhanced by epithelial soluble factors. Pre-treatment of stromal cells with TGF-b1 enhanced this migratory stimulus by elevating NOX4 expression and intracellular ROS production. TGF-b1 seems to be a major component of the epithelial soluble factors that stimulate NOX4 expression. CONCLUSIONS: Our results have identified that an increased stromal oxidative status, mainly provided by an elevated NOX4 expression, is a permissive element in the acquisition of epithelial migratory properties. The capacity of stromal cells to modify their intracellular ROS production, and accordingly, to increase epithelial motility, seems to depend on epithelial soluble factors among which TGF-b1 have a decisive role.This work was supported by the grant (1080196 to JM) from the Fondo Nacional de Ciencia y Tecnologı´a (FONDECYT) of Chile