114 research outputs found
Ponderomotive effects in multiphoton pair production
The Dirac-Heisenberg-Wigner formalism is employed to investigate
electron-positron pair production in cylindrically symmetric but otherwise
spatially inhomogeneous, oscillating electric fields. The oscillation
frequencies are hereby tuned to obtain multiphoton pair production in the
nonperturbative threshold regime. An effective mass as well as a
trajectory-based semi-classical analysis are introduced in order to interpret
the numerical results for the distribution functions as well as for the
particle yields and spectra. The results, including the asymptotic particle
spectra, display clear signatures of ponderomotive forces.Comment: 9 pages, 3 Tables, 3 Figure
microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity
Background:
The AKT/mammalian target of rapamycin (mTOR) signaling pathway is regulated by 17
α
-estradiol (E2)
signaling and mediates E2-induced proliferation and progesterone receptor (PgR) expression in breast cancer.
Methods and results:
Here we use deep sequencing analysis of previously published data from The Cancer
Genome Atlas to demonstrate that expression of a key component of mTOR signaling, rapamycin-insensitive
companion of mTOR (Rictor), positively correlated with an estrogen receptor-
α
positive (ER
α
+
) breast tumor signature.
Through increased microRNA-155 (miR-155) expression in the ER
α
+
breast cancer cells we demonstrate repression
of Rictor enhanced activation of mTOR complex 1 (mTORC1) signaling with both qPCR and western blot.
miR-155-mediated mTOR signaling resulted in deregulated ER
α
signalingbothinculturedcells
in vitro
and in
xenografts
in vivo
in addition to repressed PgR expression and act
ivity.FurthermoreweobservedthatmiR-155
enhanced mTORC1 signaling (observed through western
blot for increased phosphorylation on mTOR S2448) and
induced inhibition of mTORC2 signaling (evident through
repressed Rictor and tuberous sclerosis 1 (TSC1) gene
expression). mTORC1 induced deregulation of E2 signaling was confirmed using qPCR and the mTORC1-specific
inhibitor RAD001. Co-treatment of MCF7 breast cancer cells stably overexpressing miR-155 with RAD001 and E2
restored E2-induced PgR gene expression. RAD001 treatment of SCID/CB17 mice inhibited E2-induced tumorigenesis
of the MCF7 miR-155 overexpressing cell line. Finally we demonstrated a strong positive correlation between Rictor
and PgR expression and a negative correlation with Raptor expression in Luminal B breast cancer samples, a breast
cancer histological subtype known for having an altered ER
α
-signaling pathway.
Conclusions:
miRNA mediated alterations in mTOR and ER
α
signaling establishes a new mechanism for altered
estrogen responses independent of growth factor stimulation
Symbiotic Gene Activation is Interrupted by Endocrine Disrupting Chemicals
Endocrine disrupting chemicals (EDCs) include organochlorine pesticides, plastics manufacturing by-products, and certain herbicides[1]. These chemicals have been shown to disrupt hormonal signaling in exposed wildlife, lab animals, and mammalian cell culture by binding to estrogen receptors (ER-α and ER-β) and affecting the expression of estrogen responsive genes[2,3]. Additionally, certain plant chemicals, termed phytoestrogens, are also able to bind to estrogen receptors and modulate gene expression, and as such also may be considered EDCs[4]. One example of phytoestrogen action is genistein, a phytochemical produced by soybeans, binding estrogen receptors, and changing expression of estrogen responsive genes which certain studies have linked to a lower incidence of hormonally related cancers in Japanese populations[5]. Why would plants make compounds that are able to act as estrogens in the human body? Obviously, soybeans do not intentionally produce phytoestrogens to prevent breast cancer in Japanese women
Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer
Epithelial to mesenchymal transition (EMT) involves loss of an epithelial phenotype and activation of a mesenchymal one. Enhanced expression of genes associated with a mesenchymal transition includes ZEB1/2, TWIST, and FOXC1. miRNAs are known regulators of gene expression and altered miRNA expression is known to enhance EMT in breast cancer. Here we demonstrate that the tumor suppressive miRNA family, miR-200, is not expressed in triple negative breast cancer (TNBC) cell lines and that miR-200b-3p over-expression represses EMT, which is evident through decreased migration and increased CDH1 expression. Despite the loss of migratory capacity following re-expression of miR-200b-3p, no subsequent loss of the conventional miR-200 family targets and EMT markers ZEB1/2 was observed. Next generation RNA-sequencing analysis showed that enhanced expression of pri-miR-200b lead to ectopic expression of both miR-200b-3p and miR-200b-5p with multiple isomiRs expressed for each of these miRNAs. Furthermore, miR-200b-5p was expressed in the receptor positive, epithelial breast cancer cell lines but not in the TNBC (mesenchymal) cell lines. In addition, a compensatory mechanism for miR-200b-3p/200b-5p targeting, where both miRNAs target the RHOGDI pathway leading to non-canonical repression of EMT, was demonstrated. Collectively, these data are the first to demonstrate dual targeting by miR-200b-3p and miR-200b-5p and a previously undescribed role for microRNA processing and strand expression in EMT and TNBC, the most aggressive breast cancer subtype
Elevated expression of long intergenic non-coding RNA HOTAIR in a basal-like variant of MCF-7 breast cancer cells
Epigenetic regulation of gene expression is critical to phenotypic maintenance and transition of human breast cancer cells. HOX antisense intergenic RNA (HOTAIR) is a long intergenic non-coding RNA that epigenetically represses gene expression via recruitment of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase. Elevated expression of HOTAIR promotes progression of breast cancer. In the current study we examined the expression and function of HOTAIR in MCF-7-TNR cells, a derivative of the luminal-like breast cancer cell line MCF-7 that acquired resistance to TNF-α-induced cell death. The expression of HOTAIR, markers of the luminal-like and basal-like subtypes, and growth were compared between MCF-7 and MCF-7-TNR cells. These variables were further assessed upon inhibition of HOTAIR, EZH2, p38 MAPK, and SRC kinase in MCF-7-TNR cells. When compared with MCF-7 cells, MCF-7-TNR cells exhibited an increase in the expression of HOTAIR, which correlated with characteristics of a luminal-like to basal-like transition as evidenced by dysregulated gene expression and accelerated growth. MCF-7-TNR cells exhibited reduced suppressive histone H3 lysine27 trimethylation on the HOTAIR promoter. Inhibition of HOTAIR and EZH2 attenuated the luminal-like to basal-like transition in terms of gene expression and growth in MCF-7-TNR cells. Inhibition of p38 and SRC diminished HOTAIR expression and the basal-like phenotype in MCF-7-TNR cells. HOTAIR was robustly expressed in the native basal-like breast cancer cells and inhibition of HOTAIR reduced the basal-like gene expression and growth. Our findings suggest HOTAIR-mediated regulation of gene expression and growth associated with the basal-like phenotype of breast cancer cells
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