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+•   He...
The Cancer’s Playground• Hormone-driven architecture  – Pre- vs. post-Pubescence  – Cycles of proliferation and collapse (...
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 ...
Estrogen Signaling      Estrogen                                                                                          ...
Classifications• Based on cellular type:  –   ILC  –   IDC  –   DCIS  –   LCIS• Based on molecular signature:  –   Luminal...
Heterogeneity and the Stem Cell• No single pathway, no linear progression (case  of 16q).• Epithelial cells:  – Ductal or ...
TEB
MaSC of Red Death• Marker: EpCAM+CD44+CD24-/low (basal) (TIS)• CD24med/+CD49fhi/CD29hi• MaSC niche: receive hormonal cues ...
Stem Cell Hierarchy• Compartmentalization.• Pregnancy induced lobuloalveologenesis:  – Small population of alveolar-based ...
Bombonati and Sgroi (2011) J. PathologySTAT5A/B    Elf5                                                          STAT3   T...
Crucial Pathways: Wnt• RANKL and Wnt4        Medema and Vermeulen (Nature): 2011                                          ...
• Expression of nuclear β-catenin and cyclin D1  associated with poorer prognosis.• Mainly through upregulated LRP5/6, FZD...
DNA Repair                                        © Twentieth Century Fox• Seconds after DNA DSB, phosphorylation of  H2AX...
• 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•   Inhib...
•   Normal: ERα + NCOR + HDAC1 -| SNAIL2•   Basal carcinomas: high SNAIL2 mRNA•   SNAIL under control of Wnt•   Other fact...
Foubert et al. (2010) Breast Cancer Res.
Molecular Signatures• Progression model of ductal carcinoma:                                  Bombonati and Sgroi (2011) J...
• Evolution to high-grade tumors can be due to  divergent pathways.• Progression more intricate than the linear  model.   ...
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 mu...
• 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 prost...
• Two distinct stem cell populations                                            Bok and Small (2002) Nature Rev. Cancer   ...
A Unifying Theory• The estradiol-dihydrotestosterone (E-D)  model.• Aromatase => Testosterone -> Estradiol (E2) =>  telome...
References• Stingl J and Caldas C (2007) Molecular heterogeneity of breast  carcinomas and the cancer stem cell hypothesis...
Hormone driven cancers
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  • When the profiles of these four populations was compared with the previously defined breast cancer subtypes, it was found that the mammary stemcell-enriched signature was most prominent in the ‘claudin-low’ and normal-like subtypes, the mature luminal signature was found highly represented in the luminal A, luminal B and HER2 subtypes, whereas the stromal signature was associated with the ‘claudin-low’ subtype. Perhaps the most surprising finding was the correlation between the luminal progenitor signature and the basal subtype
  • However, mutations in GSK3B and APC are prevalent in colon carcinoma and endometrial cancer. Why?
  • ~10% breast cancers are hereditary12 to 13 classes using semi-supervised clustering
  • Telomerase activity in 90% PC and 88% ductal and lobular breast carcinomasSame can be said about PRa and PRbiAR and mAR binding to testosterone lower bcl-2 in prostate and so loss of PRb does not cause upregulation of bcl-2mAR also upregulated pro-apoptotic factors: Bad and FasLower levels of T were associated with worsening clinical staging, worsening histological staging and more poorly differentiated adenocarcinomas for PC
  • Transcript of "Hormone driven cancers"

    1. 1. Hormone-driven Cancers:Messengers of Destruction By: Khalil Abou-El-Ardat
    2. 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. 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. 4. Foubert et al. (2010) Breast Cancer Res.
    5. 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. 6. Estrogen Signaling Estrogen Estrogen Estrogen N Estrogen Receptor Src Ras GRB2 GRB2 SHC SHC SOS SOS Src C Raf PI3K EstrogencAMP Akt Estrogen MEKKs ReceptorPKA IKKs BCL2 eNOS Dimerization MAPKs ERK JNKs p38CREB P NO k NF- B 1/2 Estrogen BCL2 Estrogen Receptor Vasodilation PELP1 E6APAntiapoptosis 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 220C 2009 Gene DAX1 RIP140 Expression SHPProteinLounge.com Nucleus
    7. 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. 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. 9. TEB
    10. 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 ERADAM17 Amphiregulin EGFR Source: Deviantart
    11. 11. Stem Cell Hierarchy• Compartmentalization.• Pregnancy induced lobuloalveologenesis: – Small population of alveolar-based stem cells – PI-MEC – Marker: WAP – Progesterone
    12. 12. Bombonati and Sgroi (2011) J. PathologySTAT5A/B Elf5 STAT3 Tumor Microenvironment GATA3 Stingl and Caldas (2007) Nature Rev. Cancer
    13. 13. Crucial Pathways: Wnt• RANKL and Wnt4 Medema and Vermeulen (Nature): 2011 King et al. (2012) J. Biol. Chem.
    14. 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. 15. DNA Repair © Twentieth Century Fox• Seconds after DNA DSB, phosphorylation of H2AX.• Signaling cascade activated.• Platform for DNA repair• Key player: BRCA1
    16. 16. • Mutations in DNA repair pathways in other hormone-driven cancers: endometrial
    17. 17. SNAIL1/Twist1• EMT• E-cadherin loss• Role: SNAIL1 => Zn-finger TF• Involved in ductal network development• Inhibition of SNAIL => E-cadherin
    18. 18. • Normal: ERα + NCOR + HDAC1 -| SNAIL2• Basal carcinomas: high SNAIL2 mRNA• SNAIL under control of Wnt• Other factors: TGF-β, HIF-1α, IL-6
    19. 19. Foubert et al. (2010) Breast Cancer Res.
    20. 20. Molecular Signatures• Progression model of ductal carcinoma: Bombonati and Sgroi (2011) J. Pathol.
    21. 21. • Evolution to high-grade tumors can be due to divergent pathways.• Progression more intricate than the linear model. © Jayne Wilkins
    22. 22. Bombonati and Sgroi (2011) J. Pathol.
    23. 23. • Increased nodal status, high Ki67, increased tumor size and negative receptor status = poorer prognosis
    24. 24. 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
    25. 25. • Basal-like: – TP53 (80%) – RB1 – PI3K (less mutations; overexpression) – Amplification of the EGFR pathway
    26. 26. TCGA (2012) Nature
    27. 27. 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
    28. 28. • Two distinct stem cell populations Bok and Small (2002) Nature Rev. Cancer Wang et al. (2009) Nature
    29. 29. A Unifying Theory• The estradiol-dihydrotestosterone (E-D) model.• Aromatase => Testosterone -> Estradiol (E2) => telomerase• ERa homodimers• ERa upregulated Bcl-2 while ERb downregulates
    30. 30. 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
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