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