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
Hormone driven cancers
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
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 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
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
Heterogeneity and the Stem Cell• No single pathway, no linear progression (case of 16q).• Epithelial cells: – Ductal or lobular – Luminal or basal (myoepithelial)
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
Stem Cell Hierarchy• Compartmentalization.• Pregnancy induced lobuloalveologenesis: – Small population of alveolar-based stem cells – PI-MEC – Marker: WAP – Progesterone
Bombonati and Sgroi (2011) J. PathologySTAT5A/B Elf5 STAT3 Tumor Microenvironment GATA3 Stingl and Caldas (2007) Nature Rev. Cancer
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.
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. 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