Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: Implications for human breast cancer

被引:140
作者
Dankort, D
Maslikowski, B
Warner, N
Kanno, N
Kim, H
Wang, ZX
Moran, MF
Oshima, RG
Cardiff, RD
Muller, WJ
机构
[1] McMaster Univ, Inst Mol Biol & Biotechnol, Dept Biol, Hamilton, ON L8S 4K1, Canada
[2] McMaster Univ, Inst Mol Biol & Biotechnol, Dept Pathol & Mol Med, Hamilton, ON L8S 4K1, Canada
[3] McMaster Univ, Inst Mol Biol & Biotechnol, Dept Med Sci, Hamilton, ON L8S 4K1, Canada
[4] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA
[5] Burnham Inst, La Jolla, CA 92037 USA
[6] Univ Alberta, Dept Anat, Edmonton, AB T6G 2M7, Canada
[7] Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5G 1L6, Canada
关键词
D O I
10.1128/MCB.21.5.1540-1551.2001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Amplification of the Neu (ErbB-2 or HER-2) receptor tyrosine kinase occurs in 20 to 30% of human mammary carcinomas? correlating with a poor clinical prognosis, We have previously demonstrated that four (Y1144 Y1201, Y1227 and Y1253) of the five known Neu autophosphorylation sites can independently mediate transforming signals, The transforming potential of two of these mutants correlates with their capacity to recruit Grb2 directly to Y1144 (YB) or indirectly through Shc to Y1227 (YD), Here, we demonstrate that these transformation-competent neu mutants activate extracellular signal-regulated kinases and stimulate Ets3-dependent transcription. Although the transforming potential of three of these mutants (YB, YD, and YE) was susceptible to inhibition by Rap1A, a genetic antagonist of Res, the transforming potential of YC was resistant to inhibition by Rap1A To further address the significance of these ErbB-2-coupled signaling molecules in induction of mammary cancers! transgenic mice expressing mutant Neu receptors lacking the known autophosphorylation sites (NYPD) or those coupled directly to either Grb2 (YB) or Shc (YD) adapter molecules were derived. In contrast to the NYPD strains, which developed focal mammary tumors after a long latency period with low penetrance, all female mice derived from YB and YD strains rapidly developed mammary tumors. Although female mice from several independent YB or YD lines developed mammary tumors, the YB strains developed lung metastases at substantially higher rates than the YD strains. These observations argue that Grb2 and Shc play important and distinct roles in ErbB-2/Neu-induced mammary tumorigenesis and metastasis.
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页码:1540 / 1551
页数:12
相关论文
共 54 条
[1]  
Alroy I, 1999, MOL CELL BIOL, V19, P1961
[2]   Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis [J].
Andrechek, ER ;
Hardy, WR ;
Siegel, PM ;
Rudnicki, MA ;
Cardiff, RD ;
Muller, WJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (07) :3444-3449
[3]   neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer [J].
Andrulis, IL ;
Bull, SB ;
Blackstein, ME ;
Sutherland, D ;
Mak, C ;
Sidlofsky, S ;
Pritzker, KPH ;
Hartwick, RW ;
Hanna, W ;
Lickley, L ;
Wilkinson, R ;
Qizilbash, A ;
Ambus, U ;
Lipa, M ;
Weizel, H ;
Katz, A ;
Baida, M ;
Mariz, S ;
Stoik, G ;
Dacamara, P ;
Strongitharm, D ;
Geddie, W ;
McCready, D .
JOURNAL OF CLINICAL ONCOLOGY, 1998, 16 (04) :1340-1349
[4]  
Baselga J, 1999, SEMIN ONCOL, V26, P78
[5]   A SINGLE AUTOPHOSPHORYLATION SITE CONFERS ONCOGENICITY TO THE NEU/ERBB-2 RECEPTOR AND ENABLES COUPLING TO THE MAP KINASE PATHWAY [J].
BENLEVY, R ;
PATERSON, HF ;
MARSHALL, CJ ;
YARDEN, Y .
EMBO JOURNAL, 1994, 13 (14) :3302-3311
[6]   STOCHASTIC APPEARANCE OF MAMMARY-TUMORS IN TRANSGENIC MICE CARRYING THE MMTV/C-NEU ONCOGENE [J].
BOUCHARD, L ;
LAMARRE, L ;
TREMBLAY, PJ ;
JOLICOEUR, P .
CELL, 1989, 57 (06) :931-936
[7]   Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation [J].
Cheng, AM ;
Saxton, TM ;
Sakai, R ;
Kulkarni, S ;
Mbamalu, G ;
Vogel, W ;
Tortorice, CG ;
Cardiff, RD ;
Cross, JC ;
Muller, WJ ;
Pawson, T .
CELL, 1998, 95 (06) :793-803
[8]   Reovirus therapy of tumors with activated Ras pathway [J].
Coffey, MC ;
Strong, JE ;
Forsyth, PA ;
Lee, PWK .
SCIENCE, 1998, 282 (5392) :1332-1334
[9]   Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation [J].
Dankort, DL ;
Wang, ZX ;
Blackmore, V ;
Moran, MF ;
Muller, WJ .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (09) :5410-5425
[10]   THE CARBOXY-TERMINAL DOMAINS OF ERBB-2 AND EPIDERMAL GROWTH-FACTOR RECEPTOR EXERT DIFFERENT REGULATORY EFFECTS ON INTRINSIC RECEPTOR TYROSINE KINASE FUNCTION AND TRANSFORMING ACTIVITY [J].
DIFIORE, PP ;
SEGATTO, O ;
LONARDO, F ;
FAZIOLI, F ;
PIERCE, JH ;
AARONSON, SA .
MOLECULAR AND CELLULAR BIOLOGY, 1990, 10 (06) :2749-2756