Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
TMPRSS2
ERG
!
" # $
% &' ( % &)*" + ,+-
. / / +&". % " 0 "
1230!
/ +& /+. % 0&4. "
1230!
. / . % " 0 " 1230!
# % &' + ,+- . /
55 !% "! 12 30! 6 758228 5 19 :!;6 758
228 5129 + 6< = 4* %
TMPRSS2-ERG /+ /
TMPRSS2-ERG& + // +
+ 0
* // 4 )>. 1 (!725? @
! " A 4 ( %/+!* &+ 8: 4B. % ( (
( 0C @21 (!1D1?A > %/+ !* &+
/ +&& @,?;,.8881D,?;,.828812 7A@# A
&&
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
TMPRSS2-ERG & &E + / 4
+ + + 4
+ + ' && 4* *
+ + & F"4
* G/ / > * < *
+ + / TMPRSS22-ERG %
4 & / 8 /& ) & , & + *
%/ / + + 4 /
&& / 88+ + " %
& % Ets2 Bace2 *
G/ + + / *4+
/ ! )8& + * / 8 /&
& Ets2 G4 + / & / + *
/ 4 % & "! (% & 4
Ets2 + // / *
*TMPRSS2-ERG 4 /
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
C% & & 80/& ! @0!A8 / @( A
/ / & %%++4 & 0 /& & +
@ A > 3 0 + 1111 + *
ETS & 8/ % ( + ++ 4/ & ETS&
HG / 8 /+& / TMPRSS2*
& ETSERG ERG%G/ TMPRSS2
ERG + + +E / 4 "4
TMPRSS2-ERG & /+
+ + & @& OPA
% + + + & @&
O PA @87A ! * ERG + 4% 4 ( 8 /&
% @5 ?A / % + % @DA )+
& 4*TMPRSS2-ERG& +
' 0!+ @D8A !%* + 8
4 %G % ++ < + % &
/ % & TMPRSS-ERG & ( @D A &&
/ + & ++ &
& ) +/ TMPRSS2-ERG&
/ %/ + @?A
% % ( / + 4 &&
+ & / * & 8/ % ( > +/
TMPRSS2-ERG + +
%&&4 E K 4 &TMPRSS2-ERG&
% 4/ / +
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
/ % : 4 ( *TMPRSS2-ERG
& / + % *
& &+ % @2A :+ * / / *
/ / & 8 & G4 G+ / %% @A
/ / TMPRSS2-ERG& & 8/ %+
&+ / * +8& ( * &+
@ A (%+ * * /
&% 4*TMPRSS2 ERG/ /
% 4 / + *
H * TMPRSS2-ERG & G/ * + %
4/&& 8/ %( !4 & + % %+
// @ A &
4& %(
TMPRSS2-ERG F7 * /8
@0//+ : 0A % &* %/+8 // %
! 0 & ETS2 /
G/ /& % & ( @2 7A ."')
* 4 + / + & /
)!/ 9 )8( G/ @5A *
8 ( @?A > MX1 &84' "G!
/G/ + % % & %
4&(( @DA &
+ * + / && &G/ *
+ /+( /
&TMPRSS2-ERG& ( * *
+ + / TMPRSS2-ERG
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
% @1A ) 4/ 8 /& % &4
G/ & + & / /+ TMPRSS2-ERG
4/ 44+ @A &&
+ & *
>+/ 4* + + *
+ * /8 4 % @0//+ : 0A
+ && E// *
/ % 4 / + >
* +/ / // & * + 4 &
Probasin-Cre@Pb-CreA8+ 4 Pten % /%
% G/ & / ETS2/+
( / , G/ & (
%
! !
T-ERG T-3Mb-Erg + * /% @1A Pb-Cre
@Pb-Cre4A + * 4 &+ " " & .+ (
( + @"".((A / Rosa26-STOP-YFP@R26YFPA (8
/+Pten Ets2 +@PtenL/LEts2L/LA*4
&+ L 4 @L!;A ! + * + +G
4 / 8&4 %+ !+ *
//%4> !+ ( 3 (++@>!(3(A
&++ + @>.(A*&G&7 1M&+ @: A
+4/ && &++& @>:A
2
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
*&G1M&+ &* 0 1M
% ( *+4C(+/@0 A
8?1 (/
" !
&&8+4 * * .O %* 4
/ * & /% 4 @ A >.(
* 4 /&+ + * 8 !
4&& 0 *4* 2M +& ++/
4 * /+ 4 % ( !4 & >.( *
' @ /+ ?12A ! @0 (< ?7A 0"! @0+ !2 5A /7
@(+ "! 2A 8( @( 0 D2A K+ @ 4 + D2 5A
0 @0 (< 2A ."') @ 4 + 2A !( @ 4 + 2751A 0
* % < ! 4 @KA 8 * + G
0 * + + + @: A : >:
&/ * ?3+4 2M
+ 4 */+ 4 % ( !4 &>:*
Q:@ 4 +D51AK+@ 4 +D2 5A2@(% 871A
? @(% ""087A !G :8H 4 @ &
A * 4 & + +/ ) *
* !> * * K + +
@KA
# $
&&8+4 / * * + G G
! ; ( /" ++)!
7
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
)! )!* ! @ & A )!
* ) :: @R A ) E * %
! < @!A +/ * / C% )!
!+/& 0 + @)' )A / G/ /& * !&&+G
" ' 10/
%
In vivo / * /&+ /% 4
@A &/ / * "!(08 @" A
+% / % @(( 2DA (8 % &(
* & * CMV-Cre % @21 "C> &+ 3% &
>* ' &(A& 5 ( !//G+ 2G12 *
+G* 2G123 + +@3'0"A 4
H * " & & Rag28& + C* * ?
* / H
! & '' (
K( * / &+!+ /((@S2
A * 4 0 + / @0A /&
9 * & &+ +/ + + * " " ++
*1M: 0 K( * 4 4/'>#% * )! &
ETS2T 0U6K .0U7 7129 0U6K .0U7 7 * )!
@+/ % /'># )! V.0 2A &+ C/ + W , 4 *
/&+ /% 4 @ A * 5 / 8
& !4 &+(0 6/" @155A " @5A
5
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
/ B @ 51A B @D1A '!. @?A &+ 0 (<6 0
@ 2A
. + / * " G/+
K* 0 & * 0R 8 '0 ! *
/&+ 4@2A ! &+ * /&+ 48/
: .0 .:0 * < &+ G/
/& & + * +/ &+ .:0 .0 +
( G+ * D+*&
%/ 4 + @O PA ? + * % ?
& ( * * + 1
@OPA &)!* G &+ +/& ,8C%
:: 0 +K@)' )A * /+ +/& + * &
+/ G/ &+ % & :: +/ !& %
/ & + )! * 4< !&&+G '(/
.+ ' 1 0 + !& + < & * + //
+ !&&+G / > )!&&G +/+
/ / 1 % ,+/ G/
&
+ G/ /& + /
4 / ' C 4 &* +46
'0 7151
?
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Tmprss2-Erg Pten)
, /% / < & * +
+ & Tmprss2-Erg & & ( @1A > + )8+
+ ERG )! * 8 + Tmprss2
@Tmprss2-STOP-ERG (8+ G & &G STOP
% & Tmprss2-ERG & 9 % & OT-
ERGPA +< E loxP
+ Tmprss2 Erg /% * &
/ ( +4 G/ @ & OT-3Mb-
ErgP4&(8+ G & OT- -ErgP &G A
>/ & /&Pten8 4 G/&+ &*8
> / )/ @ '8>)A + G4
4// %/ 4%
& + @1A >/ &4 Pten % + 4
Pb-Cre *% + Pb-Cre;T-3Mb-Erg;PtenL/L + + %/ /
&& / + @ T- -Erg/Pten8+ A %
4 4+ & @1A +* % ( //
4 Tmprss2-Erg & G/ 4 * +
Pb-Cre;T-ERG;PtenL/L + < / //
+ & > & Pb-Cre;T-ERG;PtenL/L + %/
/ && / + @: !8 A T+/
D
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
+ 11M/ &Pb-Cre;T-3Mb-Erg;PtenL/L+ %// B
+ && + @: AW / %/
+ *E + 8 >)@.'8>)A &4 %
Pb-Cre;PtenL/L+ @: !A :+Pb-Cre;PtenL/L
+ Pb-Cre;T-ERG;PtenL/L + / & % *
* &+ >.( & + + @0"!A @: !A >
Pb-Cre;T-3Mb-Erg;PtenL/L + %/ % % / +
G/ & 0"! 4 + /7 @: !A 0 T- -Erg/Pten8
+ */ %&/ + / + ?@?A4*
%&4 / + 2@2A@: (A Pb-Cre;T-3Mb-
Erg;PtenL/L+ %// .'8>) +/ &?Y+
4 2Y 4 & 4 % Pb-Cre;PtenL/L
+ @: (A * <% % *+ + +/
& ?Y / + T* + 2Y 4 @: (A +
0"! /7 G/ @0//+ : 0!AW &&
+ * % 4 % Pb-Cre;PtenL/LPb-Cre;T-
ERG;PtenL/L+ * / &% %+ *+
&& + * &E @:
A
"*)% & + Pb-Cre;T-3Mb-Erg;PtenL/L
$ )
>.( *&+ '/* 4 G/ .'8
>) %/ 4 Pb-Cre;T-ERG;PtenL/L Pb-Cre;T-3Mb-Erg;PtenL/L
+ @0//+ : 0 A , /% / Pb-Cre;T-3Mb-
Erg;PtenL/L + + + && % % * +
1
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
%// &G4 + / & '/G/
* /&& % % + * %& '
@1A / 4 * & ' G/
&& Tmprss2-Erg& &+(8+ & "4
T-3Mb-Erg * /&+ /
+ / &+ *8& & .'8>)
@+ ' / %A / && + @+ + '
%A@0//+ : 0A ,G +)!&+
* &+ * / @ 4 ' / %
% A 4 + )! ( @0//+ : 0 !A *
%& 4 / & Tmprss2-Erg & *
&&% % (8+ @0//+ : 0 A
% ( 4 % Pb-Cre;T-3Mb-Erg;PtenL/L +
+ 4*Tmprss2 Erg
T- -Erg/Pten- $ , -
% 4 + + + % T- -
Erg/Pten8 + * /&+ G/ /& /
+ / / C */ 8+/
*G %4 /8 /+ + !
& 8 /& && 4* %/ Pb-
Cre;PtenL/L+ @ + .'8>)A Pb-Cre;T-3Mb-Erg;PtenL/L+ T /
&& + @+A .'8>)W* G .'8>) @
+ A &+ Pb-Cre;T-3Mb-Erg;PtenL/L + & @0//+
: 0A !+ && 4* /
+ @'0 !A@2A% +//% &/ 88
Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 15, 2016; DOI: 10.1158/0008-5472.CAN-15-1911 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
+ + @ "A * T- -Erg/Pten8 +
+/ Pten8 .'8>) @: ! 0//+ : 02!A
+ & " 4 & * +/ T- -Erg/Pten8
.'8>) Pten8 .'8>) @0//+ : 02 A *
+/ T- -Erg/Pten8 + .'8>) %/ + +
@0//+ : 02(A " T-