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Hormone-driven Cancers:Messengers of Destruction
By:
Khalil Abou-El-Ardat
Outline
• General Introduction:– Hormones and architecture
– Hormones and cancer
• Breast Cancer: HR- vs. HR+
• Heterogeneity and Stem Cell Theory
• Important Pathways
• Molecular Signatures
• Prostate Cancer: So far yet so close
• Unifying Theory?
The Cancer’s Playground
• Hormone-driven architecture
– Pre- vs. post-Pubescence
– Cycles of proliferation and collapse (breast)
• Role of hormones:
– Estrogen, progesterone and prolactin
– Testosterone and androstenedione
Foubert et al. (2010) Breast Cancer Res.
Breast Cancer: Sex as a Weapon
• Breast cancer in both sexes: prevalent in females, very rare in males (hormones?).
• Very heterogenous cancer.• Two broad types: HR status:
– HR+– HR-
• Three types of HR:– ER– PR– HER
Source: WHO, World Cancer Factsheet
Estrogen Signaling
C
N
cAMPAkt
BCL2PKA
NO
eNOS
NF-kB
NF-kB
BCL2
PCREB
SP1 c-Jun c-Fos Elk1
JNKs
IKKs
BRG1
PELP1E6AP
Cyclin D1
ERK
1/2
Dimerization
MEKKs
Raf
TIF2
AIB1
SRA
P6S
TRAP
220p72
RIP140DAX1
REA
PGC1
SHP
RTA
RP-A
BRCA1
HDACs
Sin3
p300
CBP
TFII
TBPTAFsRNA
POLII
Antiapoptosis
Vasodilation
Gene
Expression
Gene
Expression
Nucleus
Estrogen Receptor
Estrogen
Estrogen
Estrogen
Receptor
PI3K
ERE
MAPKs
SOS
GRB2Src
SHCSOS
Src
SHCGRB2
EstrogenEstrogen
PCREB
SRC1NCOREstrogen
Estrogen Receptor
Estrogen
Estrogen
Receptor
Estrogen
p38
Estrogen
Estrogen Receptor
Ras
2009
ProteinLounge.com
C
Classifications
• Based on cellular type:– ILC– IDC– DCIS– LCIS
• Based on molecular signature:– Luminal A– Luminal B– ErbB2 (double negative)– Basal (triple negative; ErbB2 negative)– Normal-like
ER+
Heterogeneity and the Stem Cell
• No single pathway, no linear progression (case of 16q).
• Epithelial cells:
– Ductal or lobular
– Luminal or basal (myoepithelial)
TEB
MaSC of Red Death
• Marker: EpCAM+CD44+CD24-/low (basal) (TIS)
• CD24med/+CD49fhi/CD29hi
• MaSC niche: receive hormonal cues and generate messengers to activate MaSCs
• MaSC expansion:
– IGF IGFR
– Estrogen ER
AmphiregulinADAM17 EGFR
Source: Deviantart
Stem Cell Hierarchy
• Compartmentalization.
• Pregnancy induced lobuloalveologenesis:
– Small population of alveolar-based stem cells
– PI-MEC
– Marker: WAP
– Progesterone
Bombonati and Sgroi (2011) J. Pathology
Stingl and Caldas (2007) Nature Rev. Cancer
STAT5A/B
GATA3
Elf5
Tumor MicroenvironmentSTAT3
Crucial Pathways: Wnt
• RANKL and Wnt4
Medema and Vermeulen (Nature): 2011
King et al. (2012) J. Biol. Chem.
• Expression of nuclear β-catenin and cyclin D1 associated with poorer prognosis.
• Mainly through upregulated LRP5/6, FZD7, and Wnt2; Wnt7b and Wnt10b.
• Downregulation of inhibitors: sFRP1-5 and WIF1.
DNA Repair
• Seconds after DNA DSB, phosphorylation of H2AX.
• Signaling cascade activated.
• Platform for DNA repair
• Key player: BRCA1
© Twentieth Century Fox
• Mutations in DNA repair pathways in other hormone-driven cancers: endometrial
SNAIL1/Twist1
• EMT
• E-cadherin loss
• Role: SNAIL1 => Zn-finger TF
• Involved in ductal network development
• Inhibition of SNAIL => E-cadherin
• Normal: ERα + NCOR + HDAC1 -| SNAIL2
• Basal carcinomas: high SNAIL2 mRNA
• SNAIL under control of Wnt
• Other factors: TGF-β, HIF-1α, IL-6
Foubert et al. (2010) Breast Cancer Res.
Molecular Signatures
• Progression model of ductal carcinoma:
Bombonati and Sgroi (2011) J. Pathol.
• Evolution to high-grade tumors can be due to divergent pathways.
• Progression more intricate than the linear model.
© Jayne Wilkins
Bombonati and Sgroi (2011) J. Pathol.
• Increased nodal status, high Ki67, increased tumor size and negative receptor status = poorer prognosis
TCGA
• 35 significantly mutated genes (510 tumors).
• PIK3CA
• TP53
• Dichotomy:
– Members of p38 SAPK
– CDH1 mutations
• Heredity: ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PTEN, RAD51C
• Basal-like:
– TP53 (80%)
–RB1
–PI3K (less mutations; overexpression)
–Amplification of the EGFR pathway
TCGA (2012) Nature
The Prostate
• Case for the stem cell: CD117.
• Serum markers: PAP, PSA, uPA ... etc.
• Role of PSA and testosterone in prostate cancer.
• IGF-1 role = breast cancer
• Less complex?
• BRCA1 and risk
• Two distinct stem cell populations
Bok and Small (2002) Nature Rev. Cancer
Wang et al. (2009) Nature
A Unifying Theory
• The estradiol-dihydrotestosterone (E-D) model.
• Aromatase => Testosterone -> Estradiol (E2) => telomerase
• ERa homodimers
• ERa upregulated Bcl-2 while ERb downregulates
References
• Stingl J and Caldas C (2007) Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis Nature Rev. Cancer7: 791-799
• Joshi PA et al. (2012) Active allies: hormones, stem cells and the niche in adult mammopoiesis Trends in Endo. and Meta. 23: 299-309
• Bombonati A and Sgroi DC (2011) The molecular pathology of breast cancer progression J. Pathology 233: 307-317
• TCGA (2012) Comprehensive molecular portraits of human breast tumours Nature 490: 61-70
• Friedman AE (2007) Can a single model explain both breast cancer and prostate cancer? Theoretical Biol. and Med. Mod. 4: 28-41
• Siegel PM and Muller WJ (2010) Transcription factor regulatory networks in mammary epithelial development and tumorigenesis Oncogene 29: 2753-2759