BY 495 Seminar Presentation-Ashley Scheines
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Transcript of BY 495 Seminar Presentation-Ashley Scheines
![Page 1: BY 495 Seminar Presentation-Ashley Scheines](https://reader036.fdocuments.us/reader036/viewer/2022062503/58ed2d801a28abe72b8b4597/html5/thumbnails/1.jpg)
Estrogen and Cancer Jing Liang and Yongfeng Shang 2012
Presented by: Ashley Scheines
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Presentation Outline•Estrogen•Molecular Mechanisms of Estrogen Action•Estrogen and Carcinogenesis•Estrogen Based Cancer Therapies•Resistance to Estrogen Based Therapies•Areas of Research in Estrogen Based
Cancers for the future
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Estrogen•Three forms of Estrogen
▫E1: estrone, E2: 17β-estradiol, E3: estriol•Regulates different physiological
processes in the body, yet has been implicated in various cancers
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Estrogen Biosynthesis
Cholesterol
Available from http://www.ncbi.nlm.nih.gov/books/NBK22339
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Estrogen’s Molecular Structure
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Estrogen Production Regulation• Hypothalamic-Pituitary-
Ovarian Axis in Premenopausal Women▫ Gonadotrophin Releasing
Hormone▫ Follicle Stimulating and
Lutenizing Hormone▫ Ovarian Granulosa Cells▫ Negative Feedback
System• Aromatase in
Postmenopausal Women
Available from: http://www.merckmanuals.com/home/womens_health_issues/biology_of_the_female_reproductive_system/menstrual_cycle.html
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Estrogen Receptor Isoforms•Estrogen binds to Estrogen Receptor α
(ERα) and Estrogen Receptor (ERβ) to exert its effects in cells.
•Expressed in Uterus, Ovary, Mammary Gland, Prostate in Males, Lungs, and Brain
•Nuclear hormone receptors
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The Estrogen Receptor Domains
Kumar et al. 2011
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Models of Estrogen Action• Classical Model
▫ ER/Estrogen Complex acts as a transcription factor and binds to Estrogen Response Elements (EREs)
• Alternative Gene Activation▫ Protein-protein
interactions with other transcription factors
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ERα and ERβ Cellular Effects •Quantity of ERα and ERβ Receptors in
Cells•Regulation of Different Genes•Different Modes of Gene Regulation•Different Affinity to Estrogen/ Response to
Estrogen•Different Hormone Independent
Transcriptional Activation Domain •Heterodimer Formation
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Transcriptional Coregulators•Necessary for Estrogen/ER complex to
alter Genetic Expression•SRC-1, SRC-2, SRC-3
▫Epigenetic Changes
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Post-Translation Modifications•Modifications made to Receptors and
Coregulators influence Estrogen’s effects on cells
•Modifications to Estrogen Receptors▫Phosphorylation, Methylation, Acetylation,
Sumoylation, Ubiquitination•Modifications made to Coregulators
▫CARM1
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Identifying ER Target Genes•Hypothesis Driven Candidate Gene
Approach▫Trefoil Factor 1▫Cathepsin D
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Identifying ER Target Genes with Sequencing Technologies
Chromatin Immunoprecipitation and Genome Tiling Microarrays
Zheng et al. 2007Available from: http://learn.genetics.utah.edu/content/labs/microarray/
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Chromatin Interaction Analysis using Paired End Tag Sequencing (ChIA-PET)• Allows for identification of
chromatin loops formed in cells when estrogen binds to DNA sequences
• MCF-7 Breast Cancer Cell Line studies
• Can learn about Estrogen/ER complex and its interactions with certain genes
Li et al. 2010
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An Introduction to Estrogen and Cancer
•Women’s Health Initiative (WHI) research program
•U.S. National Toxicology Program•International Agency for Research on
Cancer•Estrogen Induced Cancers
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Genetic Changes Related to Carcinogenesis
•Estrogen/ERα complex regulates genes that lead to cell proliferation and cell cycle progression
•-c-Myc and Cyclin D1 genes▫Effectors of estrogen action at G1 to S
transition▫Molecular mechanisms of estrogen action
not fully understood▫c-Myc gene action hypothesis
•Estrogen/ERβ effect on cancer development
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Estrogen and Apoptosis•Opposing effects of Estrogen with regard
to apoptosis▫Bcl-2 and Bcl-XL expression▫Tumor cell death in treatment with high-
dose estrogen•Dual Effects of Estrogen on Apoptosis
▫Altered gene expression▫Altered intracellular signaling after
hormone deprivation
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Estrogen and Angiogenesis•Construction of blood vessels •Tumors need blood vessels to supply
nutrients and oxygen•Occurs through several steps•Estrogen Induction of Blood Vessel
Formation
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Estrogen Induced Cancer Metastasis•17β-Estradiol-ERα pathway does not
stimulate metastasis•Epithelial-Mesenchymal transition is
considered the initial step in tumor metastasis
•Upregulation of coregulators promotes metastasis
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Anti-Estrogen Therapies•70% Breast Cancers are ER-positive
breast cancers•Selective Estrogen Receptor Modulators
(SERMs)▫Tamoxifen▫Raloxifene▫Toremifene
•Fulvestrant•Aromatase Inhibitors
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Tamoxifen• First drug developed to
target estrogen receptors in ER-positive breast cancer
• ER antagonist• Different effects in breast
tissue versus other tissues ex. uterus and bone
• Reduces breast cancer recurrence and contributed to 25-30% decrease in breast cancer mortality Available from
http://maptest.rutgers.edu/drupal/?q=node/273
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Aromatase Inhibitors (AIs)•Inhibit the final step in estrogen
biosynthesis: the conversion of the androgens to estrogen
•Targeted therapy for breast cancer in postmenopausal women and endometrial cancer
•2 Types▫Type 1▫Type 2
•Anastrozole, Letrozole, Exemestane are FDA approved AIs
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Anti-Estrogen Treatment Resistance•The National Cancer Institute: >200,000
Americans are diagnosed with annually with breast cancer
• Polymorphisms in CYP2D6 gene•Abnormal Expression of ER coregulators
▫AIB1 and SRC-1•Gene alterations •Epigenetic changes
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In Summary…•Estrogen is synthesized in different
tissues in the body and has been implicated in different cancers
•It exerts its carcinogenic effects on cells through the two estrogen receptors: α and β.
•The two main treatments for ER positive cancer are the AIs and SERMs.
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Areas of Study for the Future•Can anti-estrogen therapies be used to
treat other cancers?•Development of new ERα-specific SERMs•Targeting ERβ receptor•Identifying gene sequences that can
indicate how well tissues will respond to antiestrogen therapies
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Literature Cited[1] L.R. Nelson, S. E. Bulun, Estrogen production and action, J. Am. Acad. Dermatol. 45 (2001) S116-S124[2] J.M. Berg, J.L. Tymoczko, L. Stryer, Important Derivatives of Cholesterol Include Bile Salts and Steroid
Hormones, in J.M. Berg, J.L. Tymoczko, L. Stryer, Biochemistry, fifth ed., W.H. Freeman, New York, 2002, Section 26.4. Available from http://www.ncbi.nlm.nih.gov/books/NBK22339/ Last accessed: 23 Mar 2014
[3] R.G. Brzyski, J. Knudtson (Eds.) Menstrual Cycle, http://www.merckmanuals.com/home/womens_health_issues/biology_of_the_female_reproductive_system/menstrual_cycle.html Last Accessed: 23 Mar 2014
[4] J. Liang, Y. Shang, Estrogen and Cancer, Annu. Rev. Physiol. 75 (2013) 9.1-9.16[5] C. Thomas, J-A. Gustafsson, The different roles of ER subtypes in cancer biology and therapy, Nat.Rev.Cancer11
(2011) 597-608.[6] E.M. Fox, R.J. Davis, M.A. Shupnik, ERβ in Breast Cancer – Onlooker, Passive Player, or Active Protector?,
Steroids. 73 (2008) 1039-1051.[8] Molecular Anatomy Project 2008 Available from http://maptest.rutgers.edu/drupal/?q=node/273 Last Accessed:
23 Mar 2014[9] Zheng et al.,ChIP-chip: Data, Model, and Analysis, BIOMETRICS 63 (2007) 787-796[10] Li et al. ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag
sequencing, GENOME BIOL 11 (2010) 1-13. Available from http://genomebiology.com/2010/11/2/R22[11] Kumar et al. The Dynamic Structure of the Estrogen Receptor, J. Amino Acids (2011) 7 pages[12] University of Utah Health Sciences Genetic Science Learning Center Available from
http://learn.genetics.utah.edu/content/labs/microarray/[13] S.J. Prest, F. E. B. May, and B.R. Westley, The Estrogen-regulated protein, TFF1, stimulates migration of
human breast cancer cells, The FASEB Journal 16 (2002) 592-594 Available from http://www.fasebj.org/content/16/6/592.full
[14] Shang et al. Cofactor Dynamics and Sufficiency in Estrogen Receptor-Regulated Transcription, Cell 103 (2000) 843-852 Available from http://yadda.icm.edu.pl/yadda/element/bwmeta1.element.elsevier-12c260d4-4bd7-33c3-a702-9737595902b7/c/00000186.pdf