Hsiu Ni Kung Anatomy and Cell Biology Medical school National Taiwan University Metastatic Breast Cancer Survival Rates httpcancercareplissblogspottw201107metastaticbreastcancersurvivalrateshtml ID: 933692
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Slide1
Use specific response toward environment as a selective marker for therapy in breast cancer cells.
Hsiu-Ni KungAnatomy and Cell Biology, Medical school, National Taiwan University
Slide2Slide3Metastatic Breast Cancer Survival Rates
http://cancercarepliss.blogspot.tw/2011/07/metastatic-breast-cancer-survival-rates.html
Slide4Slide5Basement membrane
Luminal cells
Basal cells
(Aleix Prat and Charles M Perou, Nature review, 2009)
Basal progenitor
Differentiated Basal cell
Basal type tumor
Luminal type tumor
Breast tumor lineage
Slide6Basal
type tumor
Luminal
type tumor
EGFR, c-Met
(
Badve
and
Nakshatri
, J
Clin
Pathol,2009)
Slide7The Heterogeneity among Human
Breast Cancers
van de
Vijver
2002
Yi-
Hsuan
Hsiao, et al., J. cancer, 2010
Jason I
Herschkowitz
, et al.,
Genomw
biology. 2010
Genetic characteristics
Non-genetic characteristics : environmental change (stress)
Slide8Microenvironmental stresses impact tumor phenotypes
(short term) and exert selection pressure (long-term)
Slide9Microenvironments
1. Hypoxia & heterogeneity
2. Glutamine requirement
Slide101. Hypoxia & heterogeneity
The integration of the non-genetic stress signatures
with oncogenic signaling pathways
Glucose Deprived
Hypoxia
Lactic Acidosis
Acidosis
ER
PR
p53
Catenin
E2F1
PI3k
Myc
Ras
IFNa
IFNg
Akt
p63
Src
HER2
EGFR
TGFb
STAT3
TNFa
AcidosisGluc. Dep.LacAcid
Hypoxia
1143 Breast Tumors
Slide11Mixed
LumA
ER
PR
p53
Catenin
E2F1
PI3k
Myc
Ras
IFN
a
IFN
g
Akt
p63
Src
HER2
EGFR
TGF
b
STAT3
TNF
a
Acidosis
Gluc.Dep.LacAcad
Hypoxia
Subgroup
Basal
Erbb2
LumA/B
LumB
2
5
8
14
16
9
6
4
3
15
13
12
1
17
11
10
7
Microenvironment signaling identified
subtypes among ERBB2+
Tumors.
Her2
1. Hypoxia & heterogeneity
Slide12Hypoxia pathway is higher in subgroup 7.
HIF2a
1. Hypoxia & heterogeneity
Slide13Subgroup 10 has higher expression of luminal regulator genes.
GATA3
p<0.0001
1. Hypoxia & heterogeneity
(Jessica Kao, et al., 2009,
Plos
One)
high
low
Slide14Different response to HER2 inhibitor treatment in
AU565 (subgroup7) and
HCC202 (subgroup10)
.
Herceptin :
HER2 inhibitor
1. Hypoxia & heterogeneity
*
(Michael L
Gatza
et al., 2011, breast cancer research)
Slide15Mixed
LumA
ER
PR
p53
Catenin
E2F1
PI3k
Myc
Ras
IFN
a
IFN
g
Akt
p63
Src
HER2
EGFR
TGF
b
STAT3
TNF
a
Acidosis
Gluc.Dep.LacAcad
Hypoxia
Subgroup
Basal
Erbb2
LumA/B
LumB
2
5
8
14
16
9
6
4
3
15
13
12
1
17
11
10
7
Her2
1. Hypoxia & heterogeneity
Slide16Microenvironments
1. Hypoxia & heterogeneity
2. Glutamine requirement
Slide17Basal cells use more glutamine as the energy source.
ATP
glutamine
glucose
2. Glutamine requirement
Slide18Basal breast cells consume more glutamine, and exhibit canonical AAR response during glutamine deprivation
MCF7 / MDAMB231 without glutamine
What are the genetic determinants of
glutamine addiction vs. independence ?
Luminal
Basal
Canonical AAR
(ATF3/XBP1)
MCF7
MB231
MCF7
MB231
Glutamine metabolism
2. Glutamine requirement
Slide19NH3+Glutamate
Glutamine
GLUL
glutamine
synthetase
/GS
GLS 1/2
glutaminase
GLUL
(Glutamine
synthetase
, GS)
(
Jiun
-Bin Wang, et al., 2010, cancer cell)
GLS1- Liver
GLS2- Kidney
(
Glutaminase
)
GLUL
2. Glutamine requirement
Slide20Luminal-specific expression of GLUL and higher intracellular glutamine
synthetase level
GLUL
GLS1
GLS2
Breast
tumors
Breast
cancer cells
Primary breast
cells
2. Glutamine requirement
Slide21High level of GLUL confer resistance of glutamine deprivation.
MCF7: higher GLULMDAMB231: lower GLUL
(Luminal cell)
(Basal cell)
2. Glutamine requirement
Slide22Glutamine symbiosis
Glutamate
Postsynaptic neuron
Glutamate
Glutamine
Glutamine
Glutamate
Glia
cell
GS
GLS
Presynaptic
neuron
2. Glutamine requirement
Glutamine symbiosis
Slide23Luminal and basal cells have Glutamine
symbiosis
2. Glutamine requirement
Slide24GLUL
2. Glutamine requirement
Slide25Slide26Jhih-Pu
Syu
Hsiang-
Yun
Huang
Jen-
Tsan
Ashley Chi
Jeffrey R. Marks
Michael
L.
Gatza