1. Hormone-driven Cancers:
Messengers of Destruction
By:
Khalil Abou-El-Ardat

2. 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?

3. 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

4. Foubert et al. (2010) Breast Cancer Res.

5. 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

6. Estrogen Signaling
Estrogen
Estrogen Estrogen
N Estrogen
Receptor
Src Ras
GRB2 GRB2
SHC SHC
SOS SOS
Src
C
Raf
PI3K Estrogen
cAMP
Akt
Estrogen
MEKKs Receptor
PKA IKKs
BCL2 eNOS Dimerization
MAPKs
ERK
JNKs p38
CREB
P NO k
NF- B
1/2
Estrogen
BCL2 Estrogen Receptor
Vasodilation
PELP1
E6AP
Antiapoptosis
CREB
P k
NF- B SP1 c-Jun c-Fos Elk1
BRG1
Cyclin D1
Gene
Expression Estrogen TIF2
NCOR Estrogen SRC1
Sin3 AIB1
Estrogen HDACs SRA
Estrogen Receptor
TAFs TBP
RNA BRCA1 P6S
TFII p300 Estrogen Receptor
POLII PGC1
CBP RP-A TRAP
ERE p72
RTA REA 220
C 2009 Gene
DAX1 RIP140
Expression SHP
ProteinLounge.com
Nucleus

7. Classifications
• Based on cellular type:
– ILC
– IDC
– DCIS
– LCIS
• Based on molecular signature:
– Luminal A ER+
– Luminal B
– ErbB2 (double negative)
– Basal (triple negative; ErbB2 negative)
– Normal-like

8. Heterogeneity and the Stem Cell
• No single pathway, no linear progression (case
of 16q).
• Epithelial cells:
– Ductal or lobular
– Luminal or basal (myoepithelial)

9. TEB

10. 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
ADAM17 Amphiregulin EGFR
Source: Deviantart

11. Stem Cell Hierarchy
• Compartmentalization.
• Pregnancy induced lobuloalveologenesis:
– Small population of alveolar-based stem cells
– PI-MEC
– Marker: WAP
– Progesterone

12. Bombonati and Sgroi (2011) J. Pathology
STAT5A/B
Elf5
STAT3 Tumor Microenvironment
GATA3
Stingl and Caldas (2007) Nature Rev. Cancer

13. Crucial Pathways: Wnt
• RANKL and Wnt4
Medema and Vermeulen (Nature): 2011
King et al. (2012) J. Biol. Chem.

14. • 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.

15. DNA Repair
© Twentieth Century Fox
• Seconds after DNA DSB, phosphorylation of
H2AX.
• Signaling cascade activated.
• Platform for DNA repair
• Key player: BRCA1

17. • Mutations in DNA repair pathways in other
hormone-driven cancers: endometrial

18. SNAIL1/Twist1
• EMT
• E-cadherin loss
• Role: SNAIL1 => Zn-finger TF
• Involved in ductal network development
• Inhibition of SNAIL => E-cadherin

19. • Normal: ERα + NCOR + HDAC1 -| SNAIL2
• Basal carcinomas: high SNAIL2 mRNA
• SNAIL under control of Wnt
• Other factors: TGF-β, HIF-1α, IL-6

20. Foubert et al. (2010) Breast Cancer Res.

21. Molecular Signatures
• Progression model of ductal carcinoma:
Bombonati and Sgroi (2011) J. Pathol.

22. • Evolution to high-grade tumors can be due to
divergent pathways.
• Progression more intricate than the linear
model.
© Jayne Wilkins

23. Bombonati and Sgroi (2011) J. Pathol.

24. • Increased nodal status, high Ki67, increased
tumor size and negative receptor status =
poorer prognosis

25. 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

26. • Basal-like:
– TP53 (80%)
– RB1
– PI3K (less mutations; overexpression)
– Amplification of the EGFR pathway

27. TCGA (2012) Nature

28. 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

29. • Two distinct stem cell populations
Bok and Small (2002) Nature Rev. Cancer
Wang et al. (2009) Nature

30. A Unifying Theory
• The estradiol-dihydrotestosterone (E-D)
model.
• Aromatase => Testosterone -> Estradiol (E2) =>
telomerase
• ERa homodimers
• ERa upregulated Bcl-2 while ERb
downregulates

31. References
• Stingl J and Caldas C (2007) Molecular heterogeneity of breast
carcinomas and the cancer stem cell hypothesis Nature Rev. Cancer
7: 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