Breast Cancer Research Laboratory

Fox Chase, PA, United States

Breast Cancer Research Laboratory

Fox Chase, PA, United States

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Eltoum I.A.,Comprehensive Cancer Center | Desmond R.A.,Comprehensive Cancer Center | Desmond R.A.,University of Alabama at Birmingham | Russo J.,Breast Cancer Research Laboratory | Lamartiniere C.A.,Comprehensive Cancer Center
Environmental Health Perspectives | Year: 2010

Background: Bisphenol A (BPA) is a ubiquitous environmental chemical with reported endocrine-disrupting properties.Objective: Our goal in this study was to determine whether prenatal exposure to BPA predisposes the adult rat mammary gland to carcinogenesis. Methods: Pregnant rats were treated orally with 0, 25, or 250 μg BPA/kg body weight (BW) from gestation day (GD) 10 to GD21. For tumorigenesis experiments, prenatally exposed female offspring received a single gavage of 7,12-dimethylbenz(a)anthracene (DMBA; 30 mg/kg BW) on postnatal day (PND) 50, or PND100.Results: Prenatal exposure of the dam to 250 μg BPA/kg BW combined with a single exposure of female offspring to DMBA on PND100, but not on PND50, significantly increased tumor incidence while decreasing tumor latency compared with the control group. Prenatal exposure of the dam to 250 μg BPA/kg BW, in the absence of DMBA to the female offspring, increased cell proliferation and elicited differential effects at the protein level at PND100 compared with PND50. Differentially regulated proteins in the mammary gland included estrogen receptor-α, progesterone receptor-A, Bcl-2, steroid receptor coactivators, epidermal growth factor receptor, phospho-insulin-like growth factor 1 receptor, and phospho-Raf.Conclusions: Our study demonstrates that oral prenatal exposure to BPA increases mammary cancer susceptibility in offspring and shifts the window of susceptibility for DMBA-induced tumorigenesis in the rat mammary gland from PND50 to PND100. These changes are accompanied by differential effects of prenatal BPA exposure on the expression of key proteins involved in cell proliferation.

Betancourt A.M.,University of Alabama at Birmingham | Wang J.,University of Alabama at Birmingham | Jenkins S.,University of Alabama at Birmingham | Mobley J.,University of Alabama at Birmingham | And 2 more authors.
Journal of Nutrition | Year: 2012

Through our diet, weare exposed to numerous natural andman-made chemicals, including polyphenols with hormone-like properties. The most abundant hormonally active polyphenols are characterized as weak estrogens. These chemicals are hypothesized to interfere with signaling pathways involved in important diseases such as breast cancer, which in most cases is initially estrogen dependent. Two such chemicals are bisphenol A (BPA), a plasticizer, and genistein, a component of soy. In spite of both possessing estrogenic properties, BPA and genistein yield different health outcomes. The exposure of rats during the prepubertal period to BPA increases the susceptibility of adult animals formammary cancer development, whereas genistein decreases this susceptibility in a chemically induced model. Because both BPA and genistein possess estrogenic properties, it is certainly plausible that additional mechanisms are affected by these chemicals. Hence, it was our goal to investigate at the protein level how exposure to these 2 chemicals can contribute tomammary cancer causation as opposed to cancer chemoprevention. Using 2-dimensional gel electrophoresis followed by MS analysis, we identified differentially regulated proteins from the mammary glands of rats prepubertally exposed to BPA and genistein. Following protein identification, we used immunoblotting techniques to validate the identity and regulation of these proteins and to identify downstream signaling proteins. Our studies highlight the importance of proteomics technology in elucidating signaling pathways altered by exposure to hormonally active chemicals and its potential value in identifying biomarkers for mammary cancer. © 2012 American Society for Nutrition.

Betancourt A.M.,University of Alabama at Birmingham | Mobley J.A.,University of Alabama at Birmingham | Russo J.,Breast Cancer Research Laboratory | Lamartiniere C.A.,University of Alabama at Birmingham
Journal of Proteomics | Year: 2010

Bisphenol A (BPA) is a ubiquitous environmental contaminant with established endocrine disruptor properties. The objective of our study was to determine the effects of prenatal exposure to BPA on the rat mammary gland proteome in postnatal rats as a first step toward the investigation of translational biomarkers of susceptibility in the human population. Pregnant rats were treated orally with 0, 25 or 250 μg BPA/kg body weight from days 10 to 21 post-conception. Female offspring were euthanized at 21 and 50 days, and mammary glands were collected. Proteomic analysis was conducted using 2-DE, followed by a combination of MALDI-TOF-TOF and LC-MS/MS, which led to the identification of 21 differentially abundant proteins including vimentin, SPARC and 14-3-3. Western blot analysis of key downstream signaling proteins demonstrated increased phospho-AKT, c-Raf, phospho-ERKs-1 and 2, but decreased TGF-β in mammary glands of 50 day old rats exposed prenatally to BPA. Our studies indicate for the first time that key proteins involved in signaling pathways such as cellular proliferation are regulated at the protein level by BPA. This data is expected to aid in the understanding of how BPA may be influencing the susceptibility of the mammary gland to cancer transformation. © 2010 Elsevier B.V. All rights reserved.

Hsu P.-Y.,Ohio State University | Hsu H.-K.,Ohio State University | Singer G.A.C.,Ohio State University | Yan P.S.,Ohio State University | And 12 more authors.
Genome Research | Year: 2010

The current concept of epigenetic repression is based on one repressor unit corresponding to one silent gene. This notion, however, cannot adequately explain concurrent silencing of multiple loci observed in large chromosome regions. The long-range epigenetic silencing (LRES) can be a frequent occurrence throughout the human genome. To comprehensively characterize the influence of estrogen signaling on LRES, we analyzed transcriptome, methylome, and estrogen receptor alpha (ESR1)-binding datasets from normal breast epithelia and breast cancer cells. This "omics" approach uncovered 11 large repressive zones (range, 0.35-5.98 megabases), including a 14-gene cluster located on 16p11.2. In normal cells, estrogen signaling induced transient formation of multiple DNA loops in the 16p11.2 region by bringing 14 distant loci to focal ESR1-docking sites for coordinate repression. However, the plasticity of this free DNA movement was reduced in breast cancer cells. Together with the acquisition of DNA methylation and repressive chromatin modifications at the 16p11.2 loci, an inflexible DNA scaffold may be a novel determinant used by breast cancer cells to reinforce estrogen-mediated repression. © 2010 by Cold Spring Harbor Laboratory Press.

Signori C.,Pennsylvania State University | El-Bayoumy K.,Pennsylvania State University | Russo J.,Breast Cancer Research Laboratory | Thompson H.J.,Colorado State University | And 3 more authors.
Cancer Research | Year: 2011

Despite the perception that omega-3 fatty acids (n-3 FA) protect against breast cancer, epidemiologic studies have yielded inconsistent results. Although preclinical data have been, in general, more supportive of a protective effect of n-3 FA on breast cancer, inconsistencies still remain, which preclude definite conclusions or in-depth mechanistic investigations despite 30 years of research in this area. In this review, we discuss key variables that may account for inconsistencies of results across preclinical studies and provide recommendations for future experiments testing the chemopreventive effect of n-3 FAs in breast cancer, as part of a multiagent approach under rigorously controlled conditions. ©2011 AACR.

Fernandez S.V.,Breast Cancer Research Laboratory | Russo J.,Breast Cancer Research Laboratory
Toxicologic Pathology | Year: 2010

There is growing concern that estrogenic environmental compounds that act as endocrine-disrupting chemicals might potentially have adverse effects on hormone-sensitive organs such as the breast. This concern is further fueled by evidence indicating that natural estrogens, specifically 17β-estradiol, are important factors in the initiation and progression of breast cancer. We have developed an in vitro-in vivo model in which we have demonstrated the carcinogenicity of E2 in human breast epithelial cells MCF-10F. Hypermethylation of NRG1, STXBP6, BMP6, CSS3, SPRY1, and SNIP were found at different progression stages in this model. The use of this powerful and unique model has provided a tool for exploring whether bisphenol A and butyl benzyl phthalate have relevance in the initiation of breast cancer. These studies provide firsthand evidence that the natural estrogen 17β-estradiol and xenoestrogenic substances like bisphenol A are able to induce neoplastic transformation in human breast epithelial cells. Copyright © 2010 by The Author(s).

Chen J.-Q.,Breast Cancer Research Laboratory | Chen J.-Q.,Gold Belt Falcon LLC | Russo J.,Breast Cancer Research Laboratory
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2012

A common set of functional characteristics of cancer cells is that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even in the presence of oxygen compared to that of normal cells (Warburg's Effects). In addition, cancer cells exhibit substantial alterations in several energy metabolism pathways including glucose transport, tricarboxylic acid (TCA) cycle, glutaminolysis, mitochondrial respiratory chain oxidative phosphorylation and pentose phosphate pathway (PPP). In the present work, we focused on reviewing the current knowledge about the dysregulation of the proteins/enzymes involved in the key regulatory steps of glucose transport, glycolysis, TCA cycle and glutaminolysis by several oncogenes including c-Myc and hypoxia inducible factor-1 (HIF-1) and tumor suppressor, p53, in cancer cells. The dysregulation of glucose transport and energy metabolism pathways by oncogenes and lost functions of the tumor suppressors have been implicated as important biomarkers for cancer detection and as valuable targets for the development of new anticancer therapies. © 2012 Elsevier B.V.

Russo J.,Breast Cancer Research Laboratory | Russo I.H.,Breast Cancer Research Laboratory
Advances in Experimental Medicine and Biology | Year: 2011

MCF-10F, an ERα negative human breast epithelial cell line derived from normal breast tissue, is able to form ductal structures in a tridimensional collagen matrix system. MCF-10F cells that are estrogen transformed (trMCF cells) progressively express phenotypes of in vitro cell transformation, including colony formation in agar methocel and loss of the ductulogenic capacity. Selection of these trMCF cells for invasiveness identified cells (bcMCF) that formed tumors in severe combined immunodeficient mice. The cell lines derived from those tumors (caMCF) were poorly differentiated ER, PR, and ERBB2 negative adenocarcinomas. These characteristics are similar to the human basal cell-like carcinomas. This in vitro-in vivo model demonstrates the importance of the basal cell type as a stem cell that reconstitutes the branching pattern of the breast and that is also target of a carcinogenic insult leading to transformation and cancer. © 2011 Springer Science+Business Media, LLC.

Russo I.H.,Breast Cancer Research Laboratory | Russo J.,Breast Cancer Research Laboratory
Journal of Mammary Gland Biology and Neoplasia | Year: 2011

Breast cancer is the malignant disease most frequently diagnosed in women of all races and nationalities. Since the 1970s the worldwide incidence of this disease has increased 30-40% in postmenopausal women, in whom, paradoxically, the risk of developing breast cancer is significantly reduced by an early first full term pregnancy (FTP) as compared to nulliparous and late parous women. Although the cause of breast cancer is not known, the mechanisms mediating the protection conferred by an early FTP have been identified to reside in the breast itself, and to be modulated by endogenous and environmental exposures that might negatively affect this organ during specific windows in its development that extend from prenatal life until the first pregnancy. Soon after conception the embryo initiates the production of human chorionic gonadotropin (hCG), the glycoprotein hormone that is diagnostic of pregnancy. HCG in conjunction with ovarian steroid hormones primes the hypothalamic neuroendocrine system for maintaining the pregnancy. Higher levels of hCG during the first trimester of pregnancy have been associated with a reduction in maternal breast cancer incidence after age 50. In preclinical studies it has been demonstrated that both FTP and hCG treatment of virgin rats prevent the development of chemically-induced mammary tumors, a phenomenon mediated by the differentiation of the mammary gland epithelial cells prior to carcinogen exposure. Complete differentiation proceeds through complex morphological, physiological and molecular changes that occur during pregnancy and lactation, that ultimately result in increased DNA repair capabilities of the mammary epithelium, activation of genes controlling differentiation and programmed cell death and imprinting in the breast epithelium a specific and permanent genomic signature of pregnancy. This signature is indicative of a reduced breast cancer risk and serves as a molecular biomarker of differentiation for evaluating the potential use of chemopreventive agents. © Springer Science+Business Media, LLC 2011.

Fernandez S.V.,Breast Cancer Research Laboratory | Huang Y.,University of Chicago | Snider K.E.,Breast Cancer Research Laboratory | Zhou Y.,Fox Chase Cancer Center | And 2 more authors.
International Journal of Oncology | Year: 2012

It has been suggested that xenoestrogens, a group of agents termed endocrine disruptors, may contribute to the development of hormone-dependent cancers, such as breast and endometrial cancers. We previously demonstrated that the xenoestrogen, bisphenol A (BPA), was able to induce the transformation in vitro of human breast epithelial cells. The normal-like human breast epithelial cell line, MCF-10F, formed tubules in collagen (3-D cultures), although after treatment with BPA (10 -5 M and 10 -6 M BPA) the cells produced less tubules (73% and 80%, respectively) and some spherical masses (27% and 20%, respectively). In the present study, expression and DNA methylation analyses were performed in these cells after exposure to BPA. These cells showed an increased expression of BRCA1, BRCA2, BARD1, CtIP, RAD51 and BRCC3, all of which are genes involved in DNA repair, as well as the downregulation of PDCD5 and BCL2L11 (BIM), both of which are involved in apoptosis. Furthermore, DNA methylation analysis showed that the BPA exposure induced the hypermethylation of BCL2L11, PARD6G, FOXP1 and SFRS11, as well as the hypomethylation of NUP98 and CtIP (RBBP8). Our results indicate that normal human breast epithelial cells exposed to BPA have increased expressions of genes involved in DNA repair in order to overcome the DNA damage induced by this chemical. These results suggest that the breast tissue of women with BRCA1 or BRCA2 mutations could be more susceptible to the effects of BPA.

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