recent research on cla and mammary cancer prevention · 2002-06-13 · inhibition of tumorigenesis...
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Recent Research on CLA and Mammary Cancer Prevention
Clement IpRoswell Park Cancer Institute
Buffalo, New York
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Inhibition of tumorigenesis in animal models by CLA
Chemical-induced mammary cancer, skinpapillomas and colon aberrant crypt foci.
Transplantable human breast cancer cellsor prostate cancer cells in SCID mice.
No inhibitory effect with AOM-induced colon cancer in rats or intestinal cancer in Apc Min mice.
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Inverse association between dietary and serum conjugated linoleic acid and risk of breast cancerin postmenopausal women
A. Aro et al. Nutr. Cancer 38: 151-157, 2000
68 premenopausal & 127 postmenopausal womendiagnosed with breast cancer, matched with 75 premenopausal & 133 postmenopausal womenfrom the general population.
In postmenopausal women, dietary/serum CLAsignificantly lower in cases than in controls, RR = 0.4 in the highest quintile.
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control
0.5% CLA
1.0% CLA
1.5% CLA
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Incorporation of CLA and LA into different lipid fractions
17%
2%
50%
4%
25%
2%
CLA LA
NL FFA PC PE PS PI
79%
3%
10%
4% 4%
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AdipocyteCLA
CLA
mammaryepithelial cells
mammary stromal cells
Neoplasticprogression
Endothelial cells
STOP
reducedangiogenesiscontributing
to tumor inhibition
STOP
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The hallmark of chemoprevention is
the ability to block clonal expansion
of transformed lesions, and if CLA is
a good anticancer agent, there should
be evidence suggestive of this attribute.
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How early in the carcinogenesis
process can the inhibitory effect
of CLA be detected?
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BrdU-labeled TEB
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Progression of mammary glandpremalignant lesion (IDP)
A B C D
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Activity of 9,11-CLA versus 10,12-CLA in inhibiting the formation of IDPs and carcinomas in the rat mammary gland
553048610,12-CLA
51304669,11-CLA
8430726control
Total yieldNo. of ratsTotal yieldNo. of ratsTreatmentCarcinoma Expt.IDP Expt.
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CLA content in mammary gland
51.8 ± 6.2—10,12-CLA
—84.2 ± 8.39,11-CLA
10,12-CLA9,11-CLACLA in dietTissue conc. (nmol/mg lipid)
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Netgrowth
Cellproliferation
Celldeath= minus
CLA proliferation & cell death
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Cancer Prevention byDairy Product Enriched in 9,11-CLA
Ip et al.
J. Nutr. 129: 2135-2142, 1999
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Rumen Tissue
Linoleic acid(c9,c12-C18:2)
CLA(c9,t11-C18:2)
CLA (c9,t11-C18:2)
∆9 desaturase
Vaccenic acid(t11-C18:1)
Vaccenic acid(t11-C18:1)
Stearic acid(C18:0)
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Vaccenic acid and CLA content in butter fat
40.5CLA
121Vaccenic acid
(g/100 g total fatty acid)
high CLAbutter
regular butter
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Can VA substitute for CLA as an anticancer agent?
Step 1: To find a dose of VA that will
produce a tissue level of CLA known
historically to be associated with mammary
cancer prevention.
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0
40
80
120
160
0
40
80
120
160
nmol
/mg
lipid
0
5
10
15
20
Dose response of vaccenic acid (VA) on the accumulation of vaccenic acid, CLA and CLA metabolites (CD 18:3 + CD 20:3 + CD 20:4) in mammary fat pad
vaccenic acid CLA CLA metabolites
CTL
1% V
A2%
VA
3% V
A
CTL
1% V
A2%
VA
3% V
A
CTL
1% V
A2%
VA
3% V
A
*
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Can VA substitute for CLA as an anticancer agent?
Step 2: To find an appropriate endpoint
in order to evaluate the efficacy of VA.
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Reduction of IDPs by VA or CLA
≤10sections
NO
. OF
IDPs
SIZE DISTRIBUTION
0
5
10
15
20control2% VA1% 9,11-CLA
11-20sections
21-30sections
31-40sections
41-50sections
>51sections
Total No.5730
27
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CLAconjugated diene – 18:2 linoleic acid (18:2)
desaturase
conjugated diene – 18:3 γ-linolenic acid (18:3)
elongase
dihomo-γ-linolenic acid (20:3)conjugated diene – 20:3
desaturase
arachidonic acid (20:4)conjugated diene – 20:4
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Arguments against the significance of CLA metabolism in the anticancer effect of CLA
Unlikely that conjugated AA will diminish the availability of phospholipid-AA which is the precursor for eicosanoid biosynthesis
Even if formed, tissue conjugated AA conc. is very low. Phospholipid distribution profile of conjugated AA is very different from that of AA
Conjugated AA not important because anticancer effect of CLA is independent of LA in the diet
Conjugated AA is found only when dietary level of LA is low
InterpretationEmpirical observationson CLA metabolism
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Future Research Directions
• What are the critical genes?• Functional significance of
CLA-responsive genes?Gene expression
• Receptors for CLA – PPAR, SREBPor others?
• Transcriptional control of activated receptors?
Signal transduction
• Role of stromal stem celldifferentiation?
• Interaction between adipocytesand epithelial cells?
Field effect of CLA
QuestionsArea