Hormonal Carcinogenesis

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Hormonal Carcinogenesis
Chin-Yo Lin MMBIO Cancer Research Workshop July
17, 2008
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Poem describing George Beatson Exceeding tall,
but built so well his height Half-disappears in
flow of chest and limb Moustache and whisker
trooper-like in trim Frank-faced, frank-eyed,
frank-hearted, always bright And always
punctual - morning, noon and night Bland as a
Jesuit, sober as a hymn Humorous, and yet
without a touch of whim Gentle and amiable, yet
full of fight. W.E. Henley
G. T. Beatson, 'Inoperable carcinoma of mamma',
Lancet, 1896,1i 104-107, 162-165. Three young
women with inoperable breast cancer were
subjected to ovariectomy and showed improvements.
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Synthetic non-steroidal estrogen
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Henderson et al., Cancer Research (1982)
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Incidents per 100,000
Henderson et al., Cancer Research (1982)
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Henderson and Feigelson, Carcinogenesis (2000)
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Henderson et al., Cancer Research (1982)
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Henderson and Feigelson, Carcinogenesis (2000)
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Image produced by Dr. William S. Messer, Jr.,
Professor of Medicinal and Biological Chemistry
at The University of Toledo
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Estrogen and ER Function in Development,
Physiology, and Diseases
Gruber, et al., NEJM (2002)
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ER-positive
ER-negative
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Aromatase Inhibitors
Image produced by Dr. William S. Messer, Jr.,
Professor of Medicinal and Biological Chemistry
at The University of Toledo
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Selective Estrogen Receptor Modulators
Riggs and Hartmann, NEJM (2003)
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Selective Estrogen Receptor Modulators
Lonard and Smith, Steroids (2002)
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Elwood Jensen
A lady with growth neoplasticThought surgical
ablation too drastic.She preferred that her
illCould be cured with a pill,Which today is no
longer fantastic.
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An Inventory of Human Nuclear Receptors
Gronemeyer, Gustafsson, and Laudet, Nat Rev Drug
Disc (2004)
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Structural and Functional Domains of Nuclear
Receptors
Gronemeyer, Gustafsson, and Laudet, Nat Rev Drug
Disc (2004)
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Molecular Mechanisms of Nuclear Receptor Functions
Gronemeyer, Gustafsson, and Laudet, Nat Rev Drug
Disc (2004)
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Inoue and Muramatsu, BBRC 2000
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Mechanisms of Transcriptional Repression by
Estrogen Receptor
Kenneth Merrell (BYU Cancer Research Fellowship
2006,2007) Kate Kmetzsch (BYU Cancer Research
Fellowship 2006,2007) Ben Newman (BYU Cancer
Research Fellowship 2006, 2007) Rick Smith (BYU
Cancer Research Fellowship 2006, 2008) Justin
Crofts (BYU Cancer Research Fellowship 2006, 2008)
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Guillaume Bourque, GIS
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• Primary estrogen responsive genes include those
  whose expressions are suppressed following
  estrogen treatment.
• ER binding sites are adjacent to suppressed
  target genes.

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Chromatin Immunoprecipitation (ChIP) Assay
ER
ER
Gene X
ERE
Real-time PCR
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Possible Mechanisms of Transcriptional Repression
NCoR
SMRT
NRIP1
X
HDACs
H3
H4
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