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Dietary beta-carotene inhibits mammary carcinogenesis in rats depending on dietary alpha-linolenic acid content.

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(1)Dietary beta-carotene inhibits mammary carcinogenesis in rats depending on dietary alpha-linolenic acid content. Virginie Maillard, Claude Hoinard, Khelifa Arab, Marie-Lise Jourdan, Philippe Bougnoux, Véronique Chajès. To cite this version: Virginie Maillard, Claude Hoinard, Khelifa Arab, Marie-Lise Jourdan, Philippe Bougnoux, et al.. Dietary beta-carotene inhibits mammary carcinogenesis in rats depending on dietary alpha-linolenic acid content.. British Journal of Nutrition, Cambridge University Press (CUP), 2006, 96 (1), pp.18-21. �inserm-00149811�. HAL Id: inserm-00149811 https://www.hal.inserm.fr/inserm-00149811 Submitted on 7 Sep 2011. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés..

(2) HAL author manuscript The British Journal of Nutrition 07/2006; 96(1): 18-21. HAL author manuscript inserm-00149811, version 1.  

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(11) HAL author manuscript inserm-00149811, version 1.  5 j  u  v    ž  ¢ ž=£ ž ž?4 ž=5 ž?j ž u ž=v ž= ž ž ž=¢ ¢ £ s¢ ¢4 ¢ 5 ¢j ¢u ¢ v ¢  ¢ž ¢ ¢ £ £.    .  . .   . .  

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(14) HAL author manuscript. £s £4 £ 5 £j £u £ v £ . inserm-00149811, version 1. £ž £ ¢ £ V4 5 Vj u v  ž ¢ V4%£ V4P V4 4 V4%5. =$" 

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(17) HAL author manuscript. V41ž V4%¢ 5 £ 5s 54. † WXWS@ { yS_ QW¡E?7@/yXC9<›{Q>=E?7zyX7Qo>R_ Q>#{VC9F{V7©>=Q;=@ >=@_,7”_xC>=E±[ 7Q{VU=@ “•7{VCDdC9SCN“•@3yF@ 93_x¤x@'9/@@ }?CD©M=C'yF@VE?I Mf_/7©>?;+yU=@+„yXC'y<7”_<yX7:{VC— tzˆ$_/QWyX¤ZC9F@*³F„yXC y/„=QWySIsƒ>?{?tzIs~%9FCV>{@'´SI0[›iy<U=@WSQ?DDcQ¤87©>?;yF@V_XyS_•³ š}?CDeM @ ˆ t‹'ˆ´ ¥"‹ ´ b%@ C9/_/Q>HJsU=7  yF@-_Xy0WXQ9·yMR“•QM9ª7:>?{7E?@ >?{@‘=Š?´093@‚d @'C yX@VE“•@C_FM?9S@V_sYBw "6¡Y ¤Z7zyXU ;o9FQM?d=7:>?;•WXC{ yXQ9n³:y<7:“•@V´WSQ9 yM?“•QM=9s;?9/Q¤ByU ‘%´PA#CN>>f] –U7 y >=@ ›•yS@V_XysWSQ9s[=7Q{NU=@ “•7{VCD1CN>oCD©›R_‚@V_"CV>=E {@VDD1{ ›={D@t ZC yXC8C9S@x@ hRd=9S@V_ _‚@VE•C_ “•@ C> i_XyXCN>oEC9SEx@'9F9SQ9't. inserm-00149811, version 1. .

(18) HAL author manuscript. 5 5 5j 5u 5 v 5  5ž 5 ¢. inserm-00149811, version 1. Vj%£ VjP Vj 4 Vj%5 Vj j Vj1u Vj%v Vj% Vj1ž Vj%¢ u=£ u u?4 u=5 u?j u u u=v u=.  A  . "M9S7©>?;y U=@i@ hRdf@ 9S7:“•@ >ySIs>=Q _/7:;?>7LWF7:{VCV>yE7WXWS@ 9/@ >?{@ 7:> ¤8@V7:;?Uy¡;?C7©> C“•Qo>?; E7c@ yXC9<›#;?9SQM?df_H¤ C_ Q[f_‚@'9<}=@VE¨³<EC'yXC">?QVy_FU=Qo¤Z>?´ t ~C'y:y› C{V7E {Q“xdfQ?_‚7zyX7Q>QRW9SC'y CE7©dfQ?_‚@HyF7_ _FM=@VI ³CV>°7:>=E?7:{VC'y<Q9QW•ER7@3y<C9X› WXC yy› C{7E 7:>yXC=@'´SI 7”_ d=9F@-_‚@ >yS@VE*7”>iªCN[=D:@+‹t1„7e>{@ β J _FMRd?d=D:@ “•@ >yXC yX7:Q>ER7LE±>=QVya{VU?CV>?;@ZyXU?7_Z{Q“d Qo_,7 yF7Q>±¤ZU?C'yF@ }=@'9PyU@YZ^sY . {VQ>yF@ >NyFIyU@msCV[DL@‹sd=9/@V_ @ >yS_1y U=@"9S@V_FMfDzyS_sWFQ9%yU=@";?9FQMRdf_s¤87zyUQMy β JZt  @m_,U=Q¤8@VE"yXU?C y yU=@"†~ Y 9FC'yX7:Qx¤ZC_ Ž tz—?]WXQDE ;o9/@ C'yX@ 9P7:>•9FC'yS_KWX@VEZyU=@Z†~Y Ž E7@/y·y UoCN>H7:>•9FC'yS_KWX@VEZyXU@Z†~ YŒ‹"E?7c@3y0C>?ExyU?C'y%y U=@Z^0Y {Q>yF@ >Ny0¤ZC_ _/7:“•7cDLC91CV“•Q>;;?9SQM?df_Nt J ¤ C_aE?@3yF@ { yS@VEQ>=D”› 7©>*D7:}@'9/_"QWª9FC'yS_a9S@ {@ 7:}=7”>?;¨y<U=@xE?7@/yXC9<› β J–_3M?d?d=D:@ “•@ >yXC yX7Q>%tRU?7_a{Q>yF@ >Ny β ¤ZC_ >=QVym_,7e;R>=7:WS7:{VC>Ny<D:›iE?7:WSWF@'9/@ >yK[=@3y<¤8@V@ >i9FC'yS_¡WX@ E*†~ YŒŽ ³Xˆ t Š‹ ‰ˆt ˆ™ ;§;iQRWªyX7_ _FM @ ´BCV>E*†~ Y®‹8E7@/y3_ ³Xˆ t Š= *ˆ tzˆ™?´·³ *ˆ tz?Žo´3t wQ#_,7:;?>=7:WS7:{VC>yZE?7:WXWF@'9/@ >={@*7©>iyM=“•QM=9x7:>={V7cE?@ >={@C yByU=@±@ >=E#QWx@ h?d @ 937”“•@ >Ny¡¤ZC_ WXQM=>=E [ @/yX¤8@V@N> ;?9SQM?df_H¤87zyXU=QMy β JZ¥†0~ Y Ž E7@/ySIB˜?— ¬7©>={V7ER@ >={@VIK> µ‹‚™§'‹'Ž$9SC yX_¤x7 y Ušy M=“•QM=9‚‘n†0~ Y ‹±E?7@/ySIB?t  *I. >  ‹?‹/§'‹ Ž³  ˆt‹‚™?´3t β J _FM?d?dDL@ “•@ >yXC'yX7:Q>•Dc@VEmyXQxCZ9F@VEM {@VE"yM“•QM=97©>?{7E?@ >{@"7©>¨9FC'yS_sWX@VE"yU=@a†~Y ŽxE?7c@3y ¥ —?ˆ tzˆ±I> *˜§'‹'Žx³ *ˆ tzˆ?´SI[RMy >Q-y17”>89SC yS_WF@VEBy<U=@P†~YŒ‹ªER7@3y ¥Ÿ—t *I> œ‹ §'‹'Žx³ *ˆ tz?—´%{Q“d=C9S@VEByFQ yU=@V7:9s9S@V_Fd=@V{ yX7”}=@Z{Q>yX9FQ?D%³X˜?— ‘ ? tz´ tVw QE?7:WSWS@ 9S@ >{@Z7©>¨y M?“•QM=9;?9FQ¤ByXU ¤ C_PQ[f_‚@'9<}=@VEx[ @3y<¤8@V@ >•9SC yS_PWX@E yU=@a†~Y ŽxCN>=Ex†~Y ‹aE7c@ yS_s¤Z7zyXUQMy β J ³~7e;M=9F@‹ ´ t β J D:@VEmyFQxC8E?@ {V9/@'C_/@VE"yM=“•QM=90;?9SQ¤By<U•7©>•9SC'yF_sWX@'E"yXU @ †~Y ŽxE7@/y³C9FQMR>=E8CxŽ?ˆ ¯E@'{V9/@ C_‚@'´[?My>oQVy17:>9SC yS_0WX@'EZyU@B†~Y ‹PE7@ y³~7e;M=9/@ ‹ ´ t U?@ “•@ C_FM=9F@QWx„+dRUoC_/@•WX9FC{ yX7:Q>+7:>*yM“•QM93_¡¤ZC_¡>?QVyZ_/7©;?>=7:WS7:{VC>yXD:›#E7WXWF@'9/@ >ya[=@/yX¤8@V@ >+;?9FQMRdf_¥  t©Ÿ šˆt©Ÿ8CN>?E•™%tz šˆt ˜  ¤"§Q•CN>?E•² β J 9S@V_Fd @'{ yF7:}=@VD”›H7:>;?9SQM?df_aWF@VE8yU=@¡†~Y Ž E?7@/y/‘ CV>?E•™t ™ #ˆ tzCN>=E  tz  ˆt ˜  ¤"§QxCV>?E8² β J+9F@-_3df@ { yS7©}=@VD”›•7:>8;?9FQMRdf_sWS@VE"yU=@a†~ Yµ‹PE?7@/y³CD:D iˆ t Š?´ t. 0 U?@#CV}@'9FCV;=@$A ¡Y {Q>yS@ >y7©>‰y M=“•QM=9/_±¤ C_ Š?Š=ˆ tz—‰d“•Q?D©§“;°d=9SQVyF@V7:>=_ CV>=E >=QVy*_/7:;R>o7cWX7{VCV>yXDc› E?7:WXWS@ 9/@ >y[=@3y<¤8@V@ >•E?7c@3yXC9X›{VQ>=E?7zyX7cQ>=_P³XEC'yXCa>?QVy_FU=Q¤¡>o´ t. ž.

(19) HAL author manuscript inserm-00149811, version 1. u ž u=¢ v £ vs v4 v 5 vj vu v v v  vž v ¢  £ s 4  5 j u  v   ž  ¢ ž=£ ž ž?4 ž=5 ž?j.     .  U?@xQ[-p @ { yF7:}=@xQW1yU=7_"_XyME›¤ C_syXQ•E?@ yF@ 9S“7:>=@x¤¡U=@3y<U=@ 9PE?7@/yXC9<›•YZ^0Y {Qo>NyF@ >ysCDzyS@ 93_syU@8@ WXWS@V{ yPQRW ?J¯Q> “¨C““C9F›œ{VC9S{V7©>=Q;@ >=@-_‚7_Vt  @d=9SQo}=7:E?@i@ }7E?@ >={@•yU?C'y J U?CE$CV>œ7©>?U?7©[ 7 yFQ9X› @ WXWS@V{ yxQ>y M=“•QM=9 β 7:>?{7cE?@ >?{@C>=E;?9/Q¤ByU+7:>i9SC yS_¡WX@'E•y<U=@9/@ {Q““@ >=E?@VE †ª~Y 9SC yX7:Q*Q?WmŽ ³™ YZ^0Y ´SI·[?MyaWXC7:D@VE•yFQ*C{ yaC_ C d=9FQ-y<@'{ yF7:}=@CV;@ >Ny¡7:>+9SC'yF_xWX@VEiC>+†~Y 9FC'yX7:Q+QW*‹•³ ‹'—  YZ^0Y ´SI0¤¡U=7:{VU#7_¡d=9/@3ycy›#WXC9ZCN[=Q}=@ d=U›=_‚7Q?DQ;=7{VCD D@ }=@VD_K7:>•UM“¨C>•E?7@/yS_Vt0U?@-_‚@ZEC'y<C¨_FMR;;@-_XyF@VEZyU?C'ys_FM={ U•C¡d=9SQVyX@ { yF7:}=@Z@ WSWF@'{ ysQW β J Q>8yM“•QM9;?9SQo¤Ky U•“C› [=@xE?@ d @ >=E?@ >yPQ>YZ^Y {Q>yS@ >ys7:>*E?7@/yS_ ICDzyU=QM;?U*Q-y<U=@ 9P>MyX9F7zyX7Q>?CDWXC{ yFQ93_aC_ _,Q{V7:C yX@VE¤Z7zyXUYZ^Y 7:>*Q?7cD”_ “•7:;?Uy17:>yF@'9FWS@ 9/@t „=7©>?{@ β JœUoC_0[=@V@ >•_/U=Qo¤Z> y<QE?7_Fd=D:C›¨CN>Ny<7Qhf7ECN>Ny³F„7@V#_

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(58) inserm-00149811, version 1. 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0. EFA 5 diet βC w/o ∗. +. 3 4 5 6 7 8 9 101112 13 14 15 16 1718. Weeks after NMU initiation. ∗. Tumour area per tumour-bearing rat (cm²). HAL author manuscript. Tumour area per tumour-bearing rat (cm²).

(59) ?2. 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0. EFA 1 diet βC w/o. +. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18. Weeks after NMU initiation. v.

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