Regulatory Mechanisms in Breast Cancer
Regulatory Mechanisms in Breast Cancer

Author: Marc E. Lippman

Publisher: Springer Science & Business Media

Published: 2012-12-06

Total Pages: 455

ISBN-13: 1461539404

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In Breast Cancer: Cellular and Molecular Biology [Kluwer Academic Pub lishers, 1988], we tried to present an introduction to the emerging basic studies on steroid receptors, oncogenes, and growth factors in the regulation of normal and malignant mammary epithelium. The response to this volume was superb, indicating a tremendous interest in basic growth regulatory mechanisms governing breast cancer and controlling its malignant progres sion. In the two years since its publication, much new and exciting in formation has been published and the full interplay of regulatory mechanisms is now beginning to emerge. We have divided this book into four sections that we hope will unify important concepts and help to crystallize areas of consensus and/or disagreement among a diverse group of basic and clinical scientists working on the disease. The first section is devoted to studies on oncogenes, antioncogenes, proliferation, and tumor prognosis. The first chapter, by Sunderland and McGuire, introduces the characteristics of breast cancer as studied by patho logists to establish prognostic outcome. Of particular interest is a new proto oncogene called HER-2 (or neu), which is rapidly becoming accepted as a valuable new tumor marker of poor prognosis. The second chapter, by Lee Bookstein and Lee, introduces the best known antioncogene, the retinoblas toma antioncogene, whose expression is sometimes lost in breast cancer. Malignant progression appears to be influenced by the balance of proto oncogene and antioncogene expression.

Lnc-EPCAM AND Lnc-BHLHE41 AS RNA REGULATORS OF BREAST CANCER AND BREAST CANCER PREVENTION
Lnc-EPCAM AND Lnc-BHLHE41 AS RNA REGULATORS OF BREAST CANCER AND BREAST CANCER PREVENTION

Author: Maria Barton

Publisher:

Published: 2017

Total Pages: 204

ISBN-13:

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The objective of this study was to unveil a novel area of gene regulation in breast cancer and breast cancer prevention through the study of a recent discovered class of genetic regulators named long non-coding RNAs (lncRNAs). LncRNAs are RNA molecules longer than 200 nucleotides that are not translated into proteins, but regulate the transcription of genes involved in different cellular processes, including differentiation, cancer initiation and progression. The link between lncRNAs and cancer is well documented in the literature. More recently, their relevance in the transcription field is beginning to be explored and their roles have been found to vary from guiding proteins to the genome to scaffolding proteins complexes needed for the transcription of a specific gene. Initial transcriptome analysis of normal breast of parous and nulliparous postmenopausal women revealed that several lncRNAs are differentially expressed in the parous breast. This observation provided evidence of a potential role of lncRNAs in the regulation of transcription and their function in pregnancy's preventive effect in reducing the lifetime risk of developing breast cancer. Specifically, RNA sequencing of healthy postmenopausal breast tissue biopsies from eight parous and eight nulliparous women using Illumina platform was performed. The sequencing results showed that there are 42 lncRNAs differentially expressed between parous and nulliparous breast tissue. These data led to the hypothesis that these novel lncRNAs may be drivers in the process of development that occurs in the mammary gland during pregnancy, providing protection against breast cancer. After analysis of these 42 lncRNAs using bioinformatics tools, review of the scientific literature, and real-time PCR analysis, two lncRNAs (lncBHLHE41 and lncEPCAM) were selected to be tested in vitro, using different molecular techniques in human epithelial breast cell lines to determine their relevance in breast cancer. This project provided novel information on lncRNAs induced by pregnancy in the breast tissue, and identified two lncRNAs as potential key regulators in breast differentiation and cancer progression. The manipulation of these lncRNAs led to evidence of their function in vitro and, using xenograft studies, we determined their relevance in vivo. Although treatment for cancer using lncRNAs as targets is in its infancy at the clinic, the advancement in knowledge and technology to study their relevance in disease could lead to the development of therapeutics for breast cancer and breast cancer prevention in the near future.

Molecular Mechanisms Underlying the Regulation of Gene Expression and Growth in Breast Cancer Cells
Molecular Mechanisms Underlying the Regulation of Gene Expression and Growth in Breast Cancer Cells

Author: Miao Sun

Publisher:

Published: 2013

Total Pages: 175

ISBN-13:

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Breast cancer is a serious public health issue, and a full understanding of its etiology and pathophysiology is a primary focus in the field. Molecularly, the combined action of a plethora of factors in multiple pathways is involved in the regulation of the breast tumoriogenic process. Characterization of a more complete spectrum of the molecular factors will provide insights into the development of new and improved diagnostic, prognostic and therapeutic tools for treating breast cancer. To this end, my studies utilize a combination of molecular biology and bioinformatic methods, to uncover the mechanisms underlying the regulation of gene expression and growth in human breast cancer cells. To investigate the molecular crosstalk of the estrogen and c-Jun N-terminal kinase 1 (JNK1) signaling pathways, I monitored the genomic localization of estrogen receptor [alpha] (ER[alpha]) and JNK1 in basal and estrogen-stimulated MCF-7 breast cancer cells. I found that JNK1 binds to the promoter of many genes. ER[alpha] is required for the binding of JNK1 to the estrogen-induced sites, and JNK1 in turn functions as a coregulator of ER[alpha]. The convergence of ER[alpha] and JNK1 at target promoters regulates estrogen-dependent gene expression, as well as downstream estrogendependent cell growth responses. Furthermore, the implication of long noncoding RNAs (lncRNAs) in breast cancer is also coming to light. I developed a computational approach that integrates information from multiple genomic datasets, and generated a comprehensive catalog of 1888 expressed lncRNA genes in MCF-7 cells. Almost half of them are first annotated in this study, and more than a quarter are estrogen-regulated. Close examination revealed many interesting features. Interestingly, cell type-specific expression of lncRNAs predicts the intrinsic molecular subtypes of breast cancer, suggesting its potential utility as prognostic marker. Lastly, by selecting lncRNAs with elevated expression in breast tumors, and whose differential expression across a wide spectrum of tissues and cell types correlates with important cell viability genes, we identified a number of lncRNAs that are required for the normal growth of human breast cancer cells. Collectively, my studies expanded our understanding of the molecular mechanisms underlying breast cancer biology, and suggested new targets for therapeutic interventions.

AACR 2016: Abstracts 1-2696
AACR 2016: Abstracts 1-2696

Author: American Association for Cancer Research (AACR)

Publisher: CTI Meeting Technology

Published: 2016-03-28

Total Pages: 1617

ISBN-13:

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The AACR Annual Meeting is a must-attend event for cancer researchers and the broader cancer community. This year's theme, "Delivering Cures Through Cancer Science," reinforces the inextricable link between research and advances in patient care. The theme will be evident throughout the meeting as the latest, most exciting discoveries are presented in every area of cancer research. There will be a number of presentations that include exciting new data from cutting-edge clinical trials as well as companion presentations that spotlight the science behind the trials and implications for delivering improved care to patients. This book contains abstracts 1-2696 presented on April 17-18, 2016, at the AACR Annual Meeting.

Investigation of DNA and RNA Markers by Novel Technologies Demonstrates DNA Content Intratumoral Heterogeneity and Long Non-coding RNA Aberrations in Breast Tumors
Investigation of DNA and RNA Markers by Novel Technologies Demonstrates DNA Content Intratumoral Heterogeneity and Long Non-coding RNA Aberrations in Breast Tumors

Author: Zhouwei Zhang

Publisher:

Published: 2014

Total Pages: 232

ISBN-13:

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BACKGROUND: Breast cancer is the most commonly diagnosed cancer and second leading cancer death cause among females in the U.S.A. About 1 in 8 women in U.S will develop invasive breast cancer over the course of her lifetime. In 2013, 234,580 new invasive breast cancer cases are expected to occur in women within the US and approximately 64,640 non-invasive carcinomas in situ were diagnosed in 2013, most of which were ductal carcinoma in situ (DCIS). Along with technological advances, a wide variety of candidate biomarkers have been proposed for cancer diagnosis and prognosis, including DNA content and non-coding RNA. Current techniques for detecting DNA content abnormalities in formalin-fixed, paraffin-embedded (FFPE) tissue samples by flow cytometric analysis have used cells recovered from [greater than or equal to]50Â[mu]m whole tissue sections. Here, in our first study, a novel core punch sampling method was investigated for assessing DNA content abnormalities and intratumoral heterogeneity in FFPE specimens. Secondly, long non-coding RNAs (lncRNAs) has been examined. LncRNA participates in a broad spectrum of biological activities by diverse mechanisms and its dysregulation is associated with tumorgenesis. Some lncRNAs may function as oncogenes (O) and others as tumor suppressor genes (TSG). To date, lncRNA has been investigated primarily by qRT-PCR and RNA sequencing. This study has examined the relationship of lncRNA expression patterns to breast tumor pathology by chromogenic in situ hybridization (CISH). METHODS: Firstly, FFPE breast carcinoma specimens were selectively targeted using 1.0 mm diameter punch needles. Extracted cores were assayed by flow cytometry using a modified-Headley method. Secondly, the lncRNA expression levels of 6 lncRNAs: HOTAIR, H19, KCNQ1OT1, MEG3, MALAT11 and Zfas1, was examined by RNAscope® CISH using FFPE breast tissue microarrays (TMAs) comprising normal adjacent epithelia (NA), DCIS, and invasive carcinoma (IC) from 46 patients. LncRNA associate polycomb complex protein EZH2 was evaluated by immunohistochemistry (IHC). LncRNA data was also compared to standard breast tumor data including ER, PR, Her2 and Ki67 IHC. SYSTAT version 11 statistical package was used to perform for all the tests. RESULTS: Following optimization experiments of the core punch flow cytometric approach, DNA index and percent S-phase fraction intratumoral heterogeneities were detected in 10/23 (44%) and 11/23 (47%) specimens respectively. The lncRNA CISH study utilized a TMA that contained 36 spots of NA breast tissues, 34 DCIS spots and 43 IC spots. HOTAIR CISH staining was significantly stronger in IC than DCIS (p

Long Non-coding 152 Protects Breast Cancer Cell from DNA Damage
Long Non-coding 152 Protects Breast Cancer Cell from DNA Damage

Author: Jiani Wang

Publisher:

Published: 2020

Total Pages: 28

ISBN-13:

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Genomic instability is a hallmark of cancer. Inducing severe DNA damage and augmenting apoptosis to destroy cancer cells is thus a major chemotherapy approach, specifically for Triple Negative Breast Cancer cell (TNBC cell). We have uncovered a previously unrecognized role for a specific long non-coding RNA 152 (lncRNA152) induced by DNA damage reagent and function in protect genome stability, significantly overexpressed in TNBC cell. Our studies provide preliminary data that lncRNA152 overexpressed in TNBC cell and could potentially serve as a TNBC diagnostic biomarker. Also, lncRNA152-depleted cells are hypersensitive to the DNA damage inducer induced by the topoisomerase II inhibitor doxorubicin. lncRNA152 expression levels increase in response to DNA damage and are significantly higher in TNBC. We conclude that lncRNA152 could serve as a TNBC diagnostic biomarker and protects TNBC cells from DNA damage, perceptively providing a powerful approach to improve chemotherapy response.

Regulation of LRIG1 Expression in Breast Cancer
Regulation of LRIG1 Expression in Breast Cancer

Author: Catalina Simion

Publisher:

Published: 2010

Total Pages:

ISBN-13: 9781124223469

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In the present study, we investigated the regulation of the leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1 - a negative regulator of the ErbB family receptor tyrosine kinases) gene expression in human breast cancer cell lines and examined both its suppression and upregulation mechanisms. We first investigated the methylation status of the CpG islands in the LRIG1 promoter and determined if demethylation by the methylase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) could restore LRIG1 expression in the cell lines. The methylation status around the promoter region of the LRIG1 was detected by bisulfite modification and subsequent PCR amplification. The messenger RNA (mRNA) and protein levels of these genes were determined by quantitative PCR (qPCR) and western blotting, respectively. We next investigated the correlation of LRIG1 levels with the estrogen receptor-alpha (ER[alpha]) in the human breast cancer cell line ZR-75-1. Meta analysis of gene expression data sets showed that LRIG1 expression is positively correlated to ER[alpha] status. Upon estradiol stimulation, LRIG1 transcript accumulates, as seen by qPCR. Tamoxifen and fulvestrant, ER[alpha] antagonists, blocked estrogen-induced LRIG1 expression, demonstrating that this is an ER[alpha] dependent event. Following depletion of endogenous LRIG1 by small interfering RNA, estrogen-dependent proliferation of ER[alpha] positive breast cancer cells is augmented. These findings suggest that LRIG1 is an estrogen-induced gene product that suppresses ER-dependent cell growth. Taken together, these analyses provide insight into the regulatory mechanisms which dictate LRIG1 expression in breast cancer cells. A detailed understanding of the mechanism by which this negative regulator is silenced in human tumours will lead to new approaches of restoring pathway function in cancerous cells, and eventually to new treatments of patients with ErbB-positive tumours.