Estrogen and Cancer Jing Liang and Yongfeng Shang 2012
Presented by: Ashley Scheines
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
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
Estrogen Biosynthesis
Cholesterol
Available from http://www.ncbi.nlm.nih.gov/books/NBK22339
Estrogen’s Molecular Structure
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
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
The Estrogen Receptor Domains
Kumar et al. 2011
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
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
Transcriptional Coregulators•Necessary for Estrogen/ER complex to
alter Genetic Expression•SRC-1, SRC-2, SRC-3
▫Epigenetic Changes
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
Identifying ER Target Genes•Hypothesis Driven Candidate Gene
Approach▫Trefoil Factor 1▫Cathepsin D
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/
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
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
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
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
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
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
Anti-Estrogen Therapies•70% Breast Cancers are ER-positive
breast cancers•Selective Estrogen Receptor Modulators
(SERMs)▫Tamoxifen▫Raloxifene▫Toremifene
•Fulvestrant•Aromatase Inhibitors
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
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
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
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.
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
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
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(2011) 597-608.[6] E.M. Fox, R.J. Davis, M.A. Shupnik, ERβ in Breast Cancer – Onlooker, Passive Player, or Active Protector?,
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