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

[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