Role of notch signalling in deveopment, cancer development and its detailed cancer cell line study for purpose of detailed targetted molecular therapeutics
The Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signaling has also been found to be associated with cancer. Understanding the regulation by Wnt signaling may serve as a paradigm for understanding the dual nature of self-renewal signals.
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are mutated or expressed at high levels. Most normal cells undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered.
ONCOGENE AND PROTOONCOGENE
P53 GENE AND ITS APPLICATION IN CANCER ETIOLOGY
TUMOUR SUPPRESSOR GENE AND BCA AND BAC GENE AND ITS APPLICATION ON THE APOPTOSIS AND DEATH RECEPTORS
The Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signaling has also been found to be associated with cancer. Understanding the regulation by Wnt signaling may serve as a paradigm for understanding the dual nature of self-renewal signals.
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are mutated or expressed at high levels. Most normal cells undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered.
ONCOGENE AND PROTOONCOGENE
P53 GENE AND ITS APPLICATION IN CANCER ETIOLOGY
TUMOUR SUPPRESSOR GENE AND BCA AND BAC GENE AND ITS APPLICATION ON THE APOPTOSIS AND DEATH RECEPTORS
p53 has been described as “GUARDIAN ANGEL OF THE GENOME”
because it performs following mechanism:
DNA Repair
Cell growth arrest
Apoptosis (programmed cell death)
P53 is also known as cellular tumour antigen Ag, phosphoprotein
P53 or tumour suppressor p53.
P53 protein is encoded by TP53.
Introduction
History
Tumor suppressor gene- pRB
- RB gene
- Role of RB in regulation of cell cycle
- Tumor associated with RB gene mutation
Tumor suppressor gene- p53
- What is p53 gene?
- Function of p53 gene
- How it regulates cell cycle
- What happen if p53 gene inactivated
- Cancer associated with p53 mutation
- Conclusion
- References
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
p53 has been described as “GUARDIAN ANGEL OF THE GENOME”
because it performs following mechanism:
DNA Repair
Cell growth arrest
Apoptosis (programmed cell death)
P53 is also known as cellular tumour antigen Ag, phosphoprotein
P53 or tumour suppressor p53.
P53 protein is encoded by TP53.
Introduction
History
Tumor suppressor gene- pRB
- RB gene
- Role of RB in regulation of cell cycle
- Tumor associated with RB gene mutation
Tumor suppressor gene- p53
- What is p53 gene?
- Function of p53 gene
- How it regulates cell cycle
- What happen if p53 gene inactivated
- Cancer associated with p53 mutation
- Conclusion
- References
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
Microbial application for biofuel productionSAIMA BARKI
Microbial application for biofuel production-Third generation of the biofuels-emerging trend to accomplish with decreasing energy resources of the world-twenty-first century- a clean and green environment to decrease the greenhouse gases and to protect the third world countriess and also the food insecurities.
Platelet derived mi r-223 promotes a phenotypicswitch in arterial injury repairSAIMA BARKI
Platelet-Derived miR-223 Promotes a Phenotypic Switch In Arterial Injury Repair, A novel therapeutic and diagnostic technique for diabetes and to gain a deeper insight into the platelet aggregation in platelets and differentiation and proliferation.
A concise and well fabricated presentation the current techniques used for plant genome editing including CRISPER/cas9 system, TALENS, TELES, ZINC FINGER NUCLEASES(ZFN), HEJ (homologous endjoing) and many other high throughout techniques along references.
Mirna biogenesis, mechanism of action, isolation protocol, and quantification...SAIMA BARKI
The concise SlideShare presentation on the miRNA biogenesis, nomenclature, specific isolation protocols, the use of novel primers for preamplification purpose, and the comparison of different methods, qPCR based quantification along the guidance of the choice of sample and a novel technique for the different clinical samples.
thyroid carcinoma with specific empahsis on papillary thyroid carcinoma, history, risk factors, involved signalling pathway of MAPK, world wide pathogenesis status, its proposed targetting, involvmetn in cancer types
Microalgal applications for biofuel productionSAIMA BARKI
Finding alternate to fossil fuels and 21st century,,
The use of microalgae as an alternate for fossil fuel, need of hour not because of political concerns but because required for the food security of next generations.
CTLA-4: IMMUNE CHECKPOINT BLOCKADE THERAPY,,,, THE 2018 NOBEL PRIZE WINNING STUDY IN THE FIELD OF PHYSIOLOGY/ MEDICINE,,, JOINTLY AWARDED TO JAMES P. ALLISON OF USA and TASAKU HONJU OF JAPAN .
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
2. CONTENT
History
Introduction
Structure
Function
Signaling pathway
Role in cancer
invitro and invivo studies
Therapeutic strategies
References
2
3. NOTCH SIGNALLING
HISTROY:
1. First discovered by T.H Morgan in 1917,, in Drosophila mellanogester, by observing
the notch phenotype in the wing of fruit fly.
2. Then identified in human also, first consideration of gene link with development
proposed by D F Pulson in 1985.
3. Spyros Artavinis-Tsakonas discovered the pathway while working on drosophilla.
Artavinis et al,. science, 1994
4. NOTCH SIGNALING: INTRODUCTION
Mechanism: lateral inhibition and contact based signaling.
Components:
Both ligand and receptor bear EGF like repeats but the number vary from one to another.
Ligand: DELTA protein, DLL 1/3/4, JAGGED 1/2
Receptor: Notch protein, Notch 1/2/3/4,
(ECD) contains several epidermal growth factor (EGF) like varying number of repeats and negative regulatory
region (NRR)
TM hydrophobic
NICD oncogenic
Both Ligand and Receptors are membrane bound single pass glycoprotein and for functionality require proteolytic
cleavage.
Chromosoaml lcation 9q34.3
34 exons
Initially equivalent level of both receptor and ligand expression, the level depend on many mechanism
expressing and of other repressing.
Notch cleavage is of central importance that change the gene expression in the nucleus.
The reason behind the cleavage of ligand delta like is unknown.
Al Husaini, et al.,2011
5. STRUCTURE OF LIGANDS AND RECEPTORS; CONSERVANCE
THROUGHOUT EVOLUTION
Michael et al., 2005
6. IMPORTANCE OF NOTCH PATHWAY
Signaling through the notch pathway, considered one of the vastly used pathway from
early embryogenesis to adult life.
Notch signaling pathway, a highly conserved pathway,
FUNCTIONAL IN:
1. Different developmental Processes,
2. Homeostatic processes,
On Notch pathway least regulatory control implication, as direct routed from
membrane to the nucleus.
Both oncogenic and tumor suppresor under differen conditions as in some function to
promotes tissue growth and cancers while in some cell death and tumour suppression.
Complex regulation for the functional outputs includes mechanisms:
1. the receptor–ligand landscape,
2. the tissue topology,
3. the nuclear environment
4. and the connectivity of the regulatory networks.Bray, et al., Nature (2006).
7. Functions: Physiological
NOTCH
Stem cell maintainance
Regulation of development
Speciation of Cell fate
Neuronal development
,
Shaolei Zang et al. 2010
7
9. DEVELOPMENTAL LOGIC
CELL TO CELL SIGNALING
Lateral inhibition:
Production of nerve cells in drosophila
An epithelial cell when develop into a nerve cell, release a signal to neighboring not to do
the same.
Amina ahmed, Shaweeta chandra, et al., 2003
10. Notch Pathway: Role In Fate
Determination
A. Inductive signaling
B. Loss and gain of signaling
pathways
Different signaling pathways result
of different interaction pattern.
Each cell of embryo is guided along
all its one developmental pathway
or another depending on:
Its history,
Its position,
Its neighboring microenvironment.
Some of these act through relaying
signals from cell surface to interior
of cell.
Amina ahmed, Shaweeta chandra, et al., 2003
11. PROTEOLYTIC CLEAVAGE OF THE NOTCH
RECEPTOR
Notch receptor: initially synthesized as single protein then
3 proteolytic cleage
1. In Golgi apparatus (S1 cleavage)
furin in its future extracellular domain converting into heterodimer and transported to the cell surface and act
as mature functional receptor, consist of 3 domains:
1. NECD
2. TM
3. NICD
Signaling starts when ligand interact with the receptor leading to furter cleavages.
2 .Cleavage after binding to ligand (S2 cleavage)
Ligand binding lead to cleavage in NECD mediated by an extracellular protease ADAM.
3. Final cleavage (S3 cleavage)
This is done by cytoplasm gamma secretase,, letting free the NICD, very close to plasma membrane,
translocated to nucleus,
Bind to TF CSL, replacing the repressor bound to CSL.
• Yamamoto et al., 2010;
• Bray, 2006;
• Kovall and Blacklow, 2010)
13. NOTCH SIGNALLING MECHANISM: PROTEOLTIC CLEAVAGE OF BOTH
LIGANDS AND RECEPTORS
1. Context based ligand binding to receptor,,Nuclear translocation:
Receptor activation by proteolytic cleavage, cleavage by γ-secretase proteolytic
cleavage.
Release of intracellular cytoplasmic domain of the NOTCH receptors.
NIC released into the cytoplasm.
NIC translocated to the nucleus, bind to cnserved DNA binding protein
RBPJϰ/CBF-1, MASTERMIND etc like transcriptional regulatory
proteins→complex→induces→expression of several genes involve in cell divisoin,
diferentiation and survival.
2. Less characterized-direct activation of signal transduuction pathway in the
cytoplasm.
13
Artavinas, et al, 1999
15. RESEMBLANCE BETWEEN THE PROTEOLYTIC CLEAVAGE OF
NOTCH RECEPTOR AND AMYLOID PRECURSOR PROETIN (APP)
15
Sheh lam, Wang Tl, 2007
16. Role In Different Cancers
(Major Types)
Cervical cancer
Breast cancer
Prostate cancer
Leukemia
Tumor promoting function in breast
cancer
Development of adenocarcinomas in the murine mammary gland
Efstratiadis et al.,2007
16
17. BREAST CANCER; THEREAPEUTIC MECHANISMS AND
RESULTS
Most commonly diagnosed malignancy
Leading cause of death in females in westren countries
Mutation:
1. Activate expression or elevate the oncogenes
2. Disrupt tumor suppressor genes
3. Molecular lesions
The notch pathway- an important role in normal breast cell development, cell fate determination and
stem cell self-renewal
The aberrant activation of this pathway is associated with breast cancer.
INHIBITION of Notch signaling by:
Gamma secretase inhibitors,
Anti-Notch1 or anti-delta-like 4 (DLL4) monoclonal antibodies
17
Guo H, et al., 2014
18. BREAST CANCER; THEREAPEUTIC MECHANISMS AND
RESULTS
RESULTS:
1. Antitumor activity in a variety of tumors, including T-cell acute lymphoblastic leukemia (T-
ALL) and solid tumors, through multiple mechanisms:
2. Induction of cell cycle arrest or apoptosis,
3. Disruption of angiogenesis
4. Upregulation of Notch1 expression has been revealed to protect breast cancer cells from
apoptosis.
TARGETS:
1. Hairy enhancer of split (Hes) genes,
2. p21,
3. cyclinD1,
4. c-Myc,
5. nuclear factor κB,
6. B-cell lymphoma-2 (Bcl-2)
Keyaerates, et al., 2016
19. INVITRO STUDY
1. Xanthohumol (XN)derived from hops (Humulus lupulus), inhibit cell growth,
Induce apoptosis in numerous types of human cancer, including breast, prostate, leukemia and colon
cancer cells.
2. NOW focusing on its ability to inhibit breast cancer cell proliferation, cell cycle arrest, apoptosis
induction in vitro and slowing tumor growth in vivo.
3.CELL LINES AND CUTRUES:
Human MCF-7, MDA-MB-231 and HEK-293T cells, h-TERT-BJ, MCF-10A and murine 4T1 cells
cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine
serum (FBS; maintained at 37°C in a humidified atmosphere of 5% CO2 in air.
19
Roy M, et al, 2007
20. XN Regulates Notch1 Signal Pathway
Activity And Downstream Targets20
↓
Zhihong sun, et al, 2017
21. XN Inhibits Cell Growth And Migration In Breast Cancer Cell
Lines:Western Blot Analysis Of c-Myc And Survivin
21
Liaking MA, et al., 2015
22. XN Treatment Is Associated With Cell Cycle Arrest And
Apoptosis;Xn Arrests The Cell Cycle In The G0/G1 Phase
22
Zhihong sun, et al, 2017
23. XN Inhibits Breast Cancer Cells By Inducing
Apoptosis:Xn Promote Apoptosis Of Breast
Cells.
23
Zhihong sun, Qimim liu, 2017
24. XN Effects Mouse Tumor Growth And Notch 1 Protein
Expression Levels In Vivo:Xn Inhibited Tumor Growth In
Vivo.24
Zhihong sun, Qimim liu, 2017
25. Therapeutic strategies:
Specific monoclonal antibodies.
Gamma secretase inhibitors.
Receptor ubiqitylation mediated strategies.
25
• Imatani et al., 2000;
• Pece et al., 2004
26. Conclusion
Notch-1 is a transmembrane receptor protein
Involve in many physiological functions through cell to cell communication
2 types of ligand families can bind to Notch-1
Majorly involve in breast cancer
Downregulation of Notch receptors expression can act as therapeutic strategy for treatment
of cancer.
26
27. REFERENCES
1..Guo H, Wu F, Wang Y, Yan C, Su W. Overexpressed ubiquitin ligase Cullin7 in breast
cancer promotes cell proliferation and invasion via down-regulating p53. Biochem
Biophys Res Commun. 2014
2. Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert C, Vanhoeij M,
Duhoux FP, Gevaert T, Simon P, et al. Phase I study of 68Ga-HER2-Nanobody for
PET/CT assessment of HER2-expression in breast carcinoma. J Nucl
3. Al-Hussaini H, Subramanyam D, Reedijk M, Sridhar SS. Notch signaling pathway as a
therapeutic target in breast cancer. Mol Cancer Ther. 2011;
4. Yuan X, Zhang M, Wu H, Xu H, Han N, Chu Q, Yu S, Chen Y, Wu K. Expression of
Notch1 correlates with breast cancer progression and prognosis. PLoS One. 2015
5. Roy M, Pear WS, Aster JC. The multifaceted role of Notch in cancer. Curr Opin Genet
Dev. 2007;17:52–59. doi: 10.1016/j.gde.2006.
6. Palmer WH, Deng WM. Ligand-independent mechanisms of Notch activity. Trends
Cell Biol. 2015
28. Cont.
7. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: Cell fate control and signal integration in
development. Science. 1999
8. Kopan R, Ilagan MX. The canonical Notch signaling pathway: Unfolding the activation
mechanism. Cell. 2009
9. Radtke F, Raj K. The role of Notch in tumorigenesis: Oncogene or tumour suppressor. Nat Rev
Cancer. 2003
10. Robinson DR, Kalyana-Sundaram S, Wu YM, Shankar S, Cao X, Ateeq B, Asangani IA, Iyer M,
Maher CA, Grasso CS, et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene
families in breast cancer. Nat Med. 2011
11. Michael Reedijk,1,2,3 Silvia Odorcic,1 Lynn Chang : High-level Coexpression of JAG1 and NOTCH1
Is Observed in Human Breast Cancer and Is Associated with Poor Overall Survival, Cancer Res 2005; 65:
(18). September 15, 2005
12. Efstratiadis A, Szabolcs M and Klinakis A: Notch, Myc and breast cancer. Cell Cycle 6: 418-429,
2007.
13. Imatani A and Callahan R: Identification of a novel NOTCH-4/INT-3 RNA species encoding an
activated gene product in certain human tumor cell lines. Oncogene 19: 223-231, 2000
14. Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V, Zurrida S, Maisonneuve P, Viale
G and DiFiore PP: Loss of negative regulation by Numb over Notch is relevant to human breast