Manna S.,Yeshiva University |
Bostner J.,Linköping University |
Sun Y.,Harvard University |
Miller L.D.,Wake forest University |
And 9 more authors.
Clinical Cancer Research | Year: 2016
Purpose: Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifentreated and adjuvant-untreated patients. Experimental Design: Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2, 000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976-1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay. Results: We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies. Conclusions: Taken together, these data show that ERRα expression predicts response to tamoxifen treatment, and ERRα could be a biomarker of tamoxifen sensitivity and a prognostic factor in TNBC. Clin Cancer Res; 22(6); 1421-31. © 2015 American Association for Cancer Research.
Basilio D.,Albert Einstein Collegeof Medicine |
Basilio D.,New York Medical College |
Kienker P.K.,Albert Einstein Collegeof Medicine |
Briggs S.W.,Albert Einstein Collegeof Medicine |
Finkelstein A.,Albert Einstein Collegeof Medicine
Journal of General Physiology | Year: 2011
Anthrax toxin is composed of three proteins: a translocase heptameric channel, (PA63)7, formed from protective antigen (PA), which allows the other two proteins, lethal factor (LF) and edema factor (EF), to translocate across a host cell's endosomal membrane, disrupting cellular homeostasis. (PA63)7 incorporated into planar phospholipid bilayer membranes forms a channel capable of transporting LF and EF. Protein translocation through the channel can be driven by voltage on a timescale of seconds. A characteristic of the translocation of LFN, the N-terminal 263 residues of LF, is its S-shaped kinetics. Because all of the translocation experiments reported in the literature have been performed with more than one LFN molecule bound to most of the channels, it is not clear whether the S-shaped kinetics are an intrinsic characteristic of translocation kinetics or are merely a consequence of the translocation in tandem of two or three LFNs. In this paper, we show both in macroscopic and single-channel experiments that even with only one LFN bound to the channel, the translocation kinetics are S shaped. As expected, the translocation rate is slower with more than one LFN bound. We also present a simple electrodiffusion model of translocation in which LFN is represented as a charged rod that moves subject to both Brownian motion and an applied electric field. The cumulative distribution of first-passage times of the rod past the end of the channel displays S-shaped kinetics with a voltage dependence in agreement with experimental data. © 2011 Basilio et al.
PubMed | Albert Einstein Collegeof Medicine
Type: Journal Article | Journal: Reproductive sciences (Thousand Oaks, Calif.) | Year: 2011
To investigate if a diagnosis of diminished ovarian reserve (DOR) is associated with a differential gene profile of ovarian granulosa cells (GCs) in infertile women undergoing in vitro fertilization (IVF).Prospective Cohort Study.Academic IVF Program.Infertile women <38 years were prospectively enrolled into 2 groups: normal ovarian reserve (NOR, follicle-stimulating hormone [FSH] < 10 mIU/mL, n = 4) and DOR (FSH 10.0 mIU/mL, n = 4).Cumulus (C) and mural (M) GCs were isolated at egg retrieval; messenger RNA was extracted and transcribed.Differential gene expression in cerebellar granule cells (CGCs) in the 2 groups was assessed by cDNA microarray. Microarray findings were validated by quantitative real-time polymerase chain reaction (qRTPCR) in CGCs and explored in multinucleated giant cells (MGCs).Of the 1256 differentially regulated genes identified in CGCs of women with DOR, the insulin-like growth factor (IGF) family was a biologically relevant gene family of a priori interest. Downregulation of IGF1 and IGF2 ligands (-3.28- and -2.54-fold, respectively), and their receptors, (-3.53- and -1.32-fold downregulation of IGF1R and IGF2R, respectively) was identified in luteinized CGCs in women with DOR compared to those with NOR. Downregulation of both IGF1 and IGF 2 ligands (-4.35- and 3.89-fold, respectively) was furthermore observed in MGCs in women with DOR compared to those with NOR; no differences in the expression of respective receptors were however observed in MGCs in the 2 groups.Components of the IGF gene family are downregulated in GCs of women with DOR. These findings maybe contributory to the reproductive compromise observed in women with DOR, and merit further exploration.
PubMed | Albert Einstein Collegeof Medicine
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2012
The molecular identity of the protein forming hemichannels at non-junctional membranes is disputed. The family of gap junction proteins, innexins, connexins, and pannexins share several common features, including permeability characteristics and sensitivity to blocking agents. Such overlap in properties renders the identification of which of these protein species actually establishes the non-junctional membrane conductance and permeability quite complicated, especially because in vertebrates pannexins and connexins have largely overlapping distributions in tissues. Recently, attempts to establish criteria to identify events that are hemichannel mediated and those to allow the distinction between connexin- from pannexin-mediated events have been proposed. Here, I present an update on that topic and discuss the most recent findings related to the nature of functional hemichannels focusing on connexin43 and pannexin1. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.