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G<E7;:!(+f!A:DGIC!FG<FD:V
!/BB@<;?9IC;F?DB9FGK!G<GK8I9I!GKK;XDE!L;:!IJDF9L9F!G<GK8I9I!;L!J:;K9LD:GC9;<Z!
G<=9;=D<DI9IZ!G<E!IDKDFCDE!9BB@<D!B9F:;D<H9:;<BD<C!F?G:GFCD:9I
C9FI!9<!.#1!
C@B;:IV!,!=K;AGK!B9F:;G::G8!G<GK8I9I!;L!C?D!C@B;:I!;<!E9LLD:D<C!E9DCG:8!:D=9BD<I!
BG8!:DHDGK!JGC?XG8I!C?GC!G:D!E9IC9<FC9HDK8!9BJGFCDE!A8!.#1V!/C!BG8!J:;H9ED!FK@DI!C;!
X?GC!LGFC;:I!XD:D!:DIJ;<I9AKD!L;:!C?D!:DF:@9CBD<C!;L!C?D!5O
YC8JD!BGF:;J?G=DI!G<
E!X?GC!LGFC;:I!BDE9GCDE!C?D!D<?G<FDE!J:;K9LD:GC9;<!G<E!G<=9;=D<DI9I!A8!.#1V!/C!BG8!
GKI;!I?DE!K9=?C!GA;@C!?;X!.#1!9<!C?D!J@AD:CGK!X9<E;X!;:!C?D!GE@KC!X9<E;X!
E9LLD:D<C9GKK8!9BJGFC!C@B;:!JGC?XG8IV
!)<DWJDFCDEK8Z!9<!C?D!#3*!15*,!B;EDKZ!XD!L;@<E!LDXD:!B9FD!DW?9A
9C9<=!
?8JD:JKGIC9F!KDI9;<I!GC!QR!XDDUI!;<!E9DC!C?G<!GC!QP!XDDUI!;<!E9DCV!%?D!BDF?G<9IBI!
L;:!C?D!E9IGJJDG:G<FD!;L!C?DID!KDI9;<I!G:D!9<C:9=@9<=V!/<!F;<C:GIC!C;!9<C:GC@B;:GK!
BGF:;J?G=DIZ!C?D!BGa;:9C8!;L!X?9F?!G:D!5O
YC8JDZ!G!?9=?!J:;J;:C9;<!;L!C?D!
![Q!?8JD:JKGI9G
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C?D8!G:D!9<H;KHDE!9<!:DI;K@C9;<!;L!KDI9;<IV!/C!X9KK!AD!GEHG<CG=D;@I!9L!XD!FG<!?G:<DII!
G<E!DWJK;9C!C?D!9<<GCD!BDF?G<9IBI!L;:!C@B;:!I@:HD9KKG<FD!GI!<;HDK!J:DHD<CGC9HD!G<E!
C?D:GJD@C9F!IC:GCD=
9DIV!1GCG!L:;B!C?DID!IC@E9DI!9KK@B9<GCDE!C?D!EDC:9BD<CGK!DLLDFCI!;L!.#1!9<!
J:DFK9<9FGK!A:DGIC!FG<FD:!B;EDKIV!/BJ;:CG<CK8Z!.#1!J:;B;CDE!C@B;:I!9<EDJD<ED<C!
;L!C?D!EDHDK;JBD<C!;L!;HD:C!;ADI9C8Z!G<E!9<!A;C?!J@AD:C8!G<E!GE@KC?;;EV!/C!GLL9:BDE!
G<;C?D:!:DGI;<!C;!
DGC!G!AGKG<FDE!E9DC!C?:;@=?;@C!;<DiI!K9LDV!.;XDHD:Z!AD?GH9;:GK!
F?G<=DI!FG<!AD!;<D!;L!C?D!B;IC!E9LL9F@KC!CGIUI!9<!?DGKC?!J:;B;C9;<V!"E@FGC9;<!G<E!
D<F;@:G=DBD<C!L:;B!?DGKC?!FG:D!J:;LDII9;<GKI!G:D!C8J9FGKK8!9<DLLDFC9HDV!+DF;=<9]9<=!
C?GC!.#1!BG8!AD!E9LL9F@KC!C
;!GH;9E!L;:!I;BDZ!L@:C?D:!@<ED:ICG<E9<=!;L!?;X!.#1!
F;<C:9A@CDI!C;!A:DGIC!FG<FD:!:9IU!G:D!:DM@9:DE!L;:!EDHDK;J9<=!J:DHD<C9;<!IC:GCD=9DI!
C;!GKKDH9GCD!C?D!DLLDFCI!;L!.#1!9<!?9=?
Y:9IU!9<E9H9E@GKIV
!!!!!!!!!!!!!!!!!!![O!!!!!!!!!!!!!!!!!!!!!!!!!"::-).2T!!!![`!14KA>F!C3
;3!^GJKG<Y5D9D:!I@:H9HGK!F@:HDI!L;:!BGBBG:8!SGT!C@B;:
YIJDF9L9F!I@:H9HGK!
G<E!SAT!;HD:GKK!I@:H9HGK!9<!#3*!B9FD!LDE!G!J@AD:CGK!9<9C9GCDE!-#1!;:!.#1!I9<FD!`!
XDDUI!;L!G=DV
!#;@:!XDDUK8!E;IDI!;L![PB=7U=!15*,!XD:D!GEB9<9ICD:DE!H9G!;:GK!
=GHG=D!L:;B![!XDDUI!;L!G=D!C;!
9<9C9GCD!C@B;:IV!.#1!I9=<9L9FG<CK8!9<F:DGIDE!15*,
Y9<E@FDE!BGBBG:8!C@B;:!9<F9ED<FD!G<E!EDF:DGIDE!C?D9:!KGCD<F8!SJmPVPQTV!.#1!GKI;!
I9=<9L9FG<CK8!9<F:DGIDE!C?D!9<F9ED<FD!;L!BG<8!;C?D:!C8JDI!;L!C@B;:IZ!9<FK@E9<=!IU9<!
C@B;:IZ!K8BJ?;BGIZ!C?8B;BGI!G<E!?DJGC9F!C@B
;:IZ!:DI@KC9<=!9<!J;;:D:!;HD:GKK!
I@:H9HGK!SJmPVPQTV
!SGT
!!SAT
!!10203040505060708090100HFD
LFD
p=0.0008
Mammary Tumor Free Survival
Time Post Initial DMBA (wks)
Percent Mammary Tumor Free (%)
1020304050020406080100HFD
LFD
Overall Survival
p<0.0001
Time Post Initial DMBA (wks)
Percent Overall Survival (%)
![e!14KA>F!C
3C3!5GF:;J?G=D!:DF:@9CBD<C!9<!15*,
Y9<E@FDE!C@B;:IV
!SGTZ!,:=Q
YZ!5QYC8JD!
;L!BGF:;J?G=DI!G:D!J:DE;B9<G<C!9<!C?D!JD:9J?D:8!G<E!C?D!FD<CD:!;L!C@B;:I!L:;B!
A;C?!-#1!G<E!.#1
YLDE!B9FDV!SATZ!
.9=?D:!J:;J;:C9;<!;L!5O
YC8JD!BGF:;J?G=DI!XD:D!
L;@<E!9<!C?D!FD<CD:!;L!.#1!C@B;:I!SQRn!.#1!HIV!en!-#1TV!S<pQ!L;:!-#1!%@B;:!
"E=DZ!<pO!L;:!-#1!%@B;:!$D<CD:h!<pR!L;:!.#1!%@B;:!"E=DZ!
<pc!L;:!.#1!%@B;:!
$D<CD:TV!
!SGT!
!!SAT
!!!!F4/80+ Arg1-
LFD Tumor EdgeLFD Tumor CenterHFD Tumor EdgeHFD Tumor Center0204060No. of  Macrophages /  Tumor Field
F4/80+, Arg1+
LFD Tumor EdgeLFD Tumor CenterHFD Tumor EdgeHFD Tumor Center02468No. of  Macrophages /  Tumor Field
![[!!14KA>F!C3P3
!(@AD:CGK!BGBBG:8!=KG<E!
F?G:GFCD:9IC9FI!9<!#3*!B9FD!;<!-#1!;:!.#1V
!SGTZ!2@BAD:!;L!CD:B9<GK!D<E!A@EI!S%"*IT!9<!J@AD:CGK!B9FD!LDE!D9C?D:!G!-#1!;:!.#1V!
SZ!JmPVP[Z!<p[!L;:!DGF?!=:;@JVT!SATZ!1@FCGK!DK;<=GC9;<!9<!J@AD:CGK!B9FD!LDE!D9C?D:!G!
-#1!;:!.#1V!Z!JmPVP[Z!<p[!L;:!DGF?!=:;@JTV
!!!SGT
!!SAT
!!!!!!!!!!!!345670510152025LFD
HFD
*Age (wk)
No. of TEBs
345678-100102030LFD
HFD
*Age (wk)
Ductal Elongation Beyond 
Inguinal Lymph Node (Arb. Unit)
![R!14KA>F!C3P!Y
B?<=Z@
[3!SFTZ!+DJ:DID<CGC9HD!X?;KD!B;@<C!9BG=DI!;L!BGBBG:8!=KG<EI!
GLCD:!O!XDDUI!;<!E9DC!GC![!XDDUI!;L!G=DV!-9<DI!9<E9FGCD!C?D!E9ICGK!DE=D!;L!C?D!
BGBBG:8!E@FCGK!C:DDV!
!!SFT!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!-#1!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!.#1
!!!!!!!!!!!!!!!!!!!!!!!!!![\!14KA>F!C3S
3!$DKK@KG:!J:;K9LD:GC9;<!GLCD:!O!XDDUI!;<!E9DCV
!.#1!I9=<9L9FG<CK8!9<F:DGIDE!
C?D!J:;J;:C9;<!;L!J:;K9LD:GC9<=!FDKKI!9<!KG:=D!E@FCIZ!IBGKK!E@FCI!G<E!%"*I!GLCD:!O!
XDDUI!;<!E9DCZ!G<E!<;!E9LLD:D<FDI!XD:D!;AID:HDE!GLCD:!e!XDDUI!;<!E9DCV!SPVP[Z!
<p[!L;:!DGF?!=:;@JTV
!!!!!!!!!!!!!!!!!!!!!!!!!2 weeks on diet
Large DuctsSmall DuctsTEBs0510152025LFD
HFD
% BrdU+ Cells
***![c!14KA>F!C3U
3!.8JD:JKGIC9F!KDI9;<I!9<!BGBBG:8!=KG<EI!<;V!O!G<E!`!GC!QP!G<E!QR!XDDUI!
;<!E9DCV
!,LCD:!QP!XDDUI!;<!E9DCZ!G!C:D<E!;L!B;:D!KDI9;<I!XD:D
!;AID:HDE!9<!.#1
YLDE!B9FD!SJpPVQOZ!<pQPTV!*8!QR!XDDUI!;L!E9DCZ!C?D!<@BAD:!;L!?8JD:JKGIC9F!KDI9;<I!9<!-#1!
G<E!.#1
YLDE!B9FD!XGI!I9B9KG:!S<pRTV
!!!SGT
!!SAT
!!!!!!10 weeks on Diet16 weeks on Diet020406080100LFD
HFD
Percent Mammary Glands 
with Hyperplastic Lesions
10 weeks on Diet16 weeks on Diet0.00.51.01.52.02.5LFD
HFD
No. of Hyperplastic Lesion 
![d!14KA>F!C3X
3!5GF:;J?G=D!:DF:@9CBD<C!GC!QP!XDDUI!G<E!QR!XDDUI!;<!E9DCV
!SGTZ!
!.#1!E9E!<;C!F?G<=D!C?D
!<@BAD:!;L!BGF:;J?G=DI!GII;F9GCDE!X9C?!<;:BGK!IC:@FC@:DIV!!
,LCD:!QP!XDDUI!;<!E9DCZ!.#1!I9=<9L9FG<CK8!:DF:@9CDE!B;:D!,:=Q
Y!5QYC8JD!;L!
BGF:;J?G=DI!SJpPVPQTZ!X?9KD!C?D!F?G<=D!9<!C?D!<@BAD:!;L!,:=Qf!5O
YBGF:;J?G=DI!
XD:D!<;C!ICGC9IC9FGKK8!I9=<9L9FG<C
!SJpPVOTV!S<p[!L;:!DGF?!=:;@JTV
!SGT
!!!!!!!!!!!!!!!!!!!!10wk on Diet
Large DuctsSmall DuctsHyperplasiaLarge DuctsSmall DuctsHyperplasia0510152025F4/80+ Arg1+
F4/80+ Arg1-
LFD                           HFD 
No. of  Macrophages / Structure
*, p=0.01
!RP!14KA>F!C3X!Y
B?<=Z@
[V!SATZ!,LCD:!QR!XDDUI!;<!E9DCZ!C?D!:DF:@9CBD<C!;L!A;C?!,:=Q
Y!5Q!
G<E!,:=Qf!5O!BGF:;J?G=DI!:DBG9<DE!DKDHGCDE!A8!.#1V!!SJpPVO!G<E!JpPVP\!L;:!5Q!
G<E!5O
YC8JDZ!:DIJDFC9HDK8TV!S<p[!L;:!DGF?!=:;@JTV
!SAT!!!!!!!16wk on Diet
Large DuctsSmall DuctsHyperplasiaLarge DuctsSmall DuctsHyperplasia051015F4/80+ Arg1+
F4/80+ Arg1-
LFD                           HFD 
No. of  Macrophages / Structure
p=0.07
!RQ!14KA>F!C3D3
!4D9=?C!=G9<!9<!15*,
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!SATZ!,LCD:!
QP!EG8I!;<!E9DC!S`Q!EG8I!;L!G=DTZ!J@AD:CGKK8!9<9C9GCDE!.#1!GC!`!XDDUI!;L!G=D!
J:;B;CDE!9<F:DGIDE!A;E8!XD9=?C!=G9<V!.#1!9<9C9GCDE!L:;B!`!XDDUI!;L!G=D!9<F:DGIDE!
J@AD:CG
K!A;E8!XD9=?C!=G9<!ADCXDD<!eVe!C;!c!XDDUI!;L!G=DV!!SGTZ!%?D!J@AD:CGK!=G9<!XGI!
K;IC!9<!B9FD!;<!.#1!GLCD:!15*,!DWJ;I@:DIV!59FD!;<!.#1!:D=G9<DE!C?D9:!K;IC!XD9=?C!
G<E!ADF;BD!?DGH9D:!C?G<!F;<C:;KI!A8!Q\!XDDUI!;L!G=D!9<!GE@KC?;;EV!*8!C?D!D<E!;L!C?D!
A;E8!XD9=?C!B
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C?D9:!-#1!F;@<CD:JG:CIV!S<oc!9<!GKK!EGCG!J;9<CITV
!SGT
!!SAT
!!!!!!!1020304010203040LFD
HFD
*, from 17 weeks onwards
*, 4.4-8 weeks
DMBA Challenge
Age (wk)
Body Weight
Pubertal Weght Gain
203040500102030LFD
HFD
*Age (d)
Body Weight
!RO!14KA>F!C3V
3!#GIC9<=!JKGIBG!=K@F;ID!G<E!9<I@K9<!KDHDKI!GC!QP!G<E!QR!XDDUI!;<!E9DCV
!SGTZ!#GIC9<=!JKGIBG!=K@F;ID!KDHDKI!XD:D!9<
F:DGIDE!9<!.#1YLDE!G<9BGKI!GLCD:!QR!XDDUI!
;<!E9DCV!SATZ!,C!G!8;@<=D:!G=DZ!GLCD:!QP!XDDUI!;<!E9DCZ!-#1
YLDE!B9FD!?GE!?9=?D:!
LGIC9<=!9<I@K9<!KDHDKIV!.9=?!HG:9G<FD!XGI!;AID:HDE!9<!LGIC9<=!JKGIBG!9<I@K9<!KDHDKI!
GB;<=!B9FD!9<!C?D!IGBD!C:DGCBD<C!=:;@JI!GC!KGCD:!C
9BD!J;9<CIZ!J;II9AK8!E@D!C;!
15*,
YGII;F9GCDE!JGC?;K;=8V
!SGT
!!SAT
!!!!!!10 weeks on Diet16 weeks on Diet0100200300400LFD
HFD
*, p=0.01
Fasting Glucose (mg/dl)
10 weeks on Diet16 weeks on Diet0.00.51.01.52.0LFD
HFD
Fasting Insulin (ng/ml)
!R`!%IHJF!C3;3!19DC!F;BJ;I9C9;<IV
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![eVeP\
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.#1YLDE!B9FD!S<p`QT!XD:D!IX9CF?DE!C;!-#1!GC!QP!XDDUI!;L!G=DV!&9B9KG:K8Z!C;!
9<HDIC9=GCD!C?D!DLLDFCI!;L!.#1!DWJ;I@:D!E@:9<=!C?D!GE@KC!X9<E;XZ!G!=:;@J!;L!-#1
YLDE!B9FD!S<p`QT!X
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LGC!E9DC!S.#1h!<p!eRTZ!G!JD:9J@AD:CGK!?9=?!LGC!E9DC!S.#1
Y-#1Z!<peOTZ!G<E!G!?9=?!LGC!
E9DC!:DIC:9FC
DE!C;!GE@KC?;;E!S-#1
Y.#1Z!<p`cTV!SGT!'<D
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I9=<9L9FG<CK8!:DE@FDE!9<!B9FD!LDE!.#1
Y-#1!G<E!-#1
Y.#1V!S-;=
Y:G<U!CDICIZ!-#1!HIV!
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Y-#1Z!Z!J!p!PVPeOh!-#1!HIV!-#1
Y.#1Z!Z!J!p!PVPPdTV!SAT!
[PPYEG8!C@B;:!L:DD!I@:
H9HGK!XGI!I9=<9L9FG<CK8!:DE@FDE!A8!K9LDK;<=!.#1!G<E!-#1
Y.#1Z!A@C!<;C!.#1
Y-#1V!S-;=
Y:G<U!CDICIZ!-#1!HIV!.#1Z!Z!J!p!PVPeRh!-#1!HIV!.#1
Y-#1Z!
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Y.#1Z!Z!J!p!PVPPRTV
!SGT
!!SAT
!!!!!01002003004000255075100LFD
HFD
LFD-HFD
HFD-LFD
Age (d)
% Mammary Tumor Free
***01002003004005006000255075100LFD
HFD
LFD-HFD
HFD-LFD
Age (d)
% Mammary Tumor Free
***!R\!!14KA>F!P3P3
!(:;J;:C9;<I!;L!C@B;:I!A8!?9IC;JGC?;K;=8!GF:;I
I!C?D!E9LLD:D<C!E9DCG:8!
:D=9BD<I!9<!*,-*7F!B9FD!:DFD9H9<=!
!"#$%
&'())
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