Enhancement of insulin-like growth factor signaling in human breast cancer:: Estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo

被引:280
作者
Lee, AV [1 ]
Jackson, JG [1 ]
Gooch, JL [1 ]
Hilsenbeck, SG [1 ]
Coronado-Heinsohn, E [1 ]
Osborne, CK [1 ]
Yee, D [1 ]
机构
[1] Univ Texas, Hlth Sci Ctr, Dept Med, Div Med Oncol, San Antonio, TX 78284 USA
关键词
D O I
10.1210/me.13.5.787
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Cross-talk between insulin-like growth factor (IGF)- and estrogen receptor (ER)-signaling pathways results in synergistic growth. We show here that estrogen enhances IGF signaling by inducing expression of three key IGF- regulatory molecules, the type I IGF receptor (IGFR1) and its downstream signaling molecules, insulin receptor substrate (IRS)-1 and IRS-2. Estrogen induction of IGFR1 and IRS expression resulted in enhanced tyrosine phosphorylation of IRS-1 after IGF-I stimulation, followed by enhanced mitogen-activated protein kinase activation. To examine whether these pathways were similarly activated in vivo, we examined MCF-7 cells grown as xenografts in athymic mice. IRS-1 was expressed at high levels in estrogen-dependent growth of MCF-7 xenografts, but withdrawal of estrogen, which decreased tumor growth, resulted in a dramatic decrease in IRS-1 expression. Finally, we have shown that high IRS-1 expression is an indicator of early disease recurrence in ER-positive human primary breast tumors. Taken together, these data not only reinforce the concept of cross-talk between IGF- and ER-signaling pathways, but indicate that IGF molecules may be critical regulators of estrogen-mediated growth and breast cancer pathogenesis.
引用
收藏
页码:787 / 796
页数:10
相关论文
共 58 条
  • [1] ABE O, 1992, LANCET, V339, P71
  • [2] Altucci L, 1996, ONCOGENE, V12, P2315
  • [3] CHARACTERIZATION AND REGULATION OF THE MOUSE INSULIN-RECEPTOR SUBSTRATE GENE PROMOTER
    ARAKI, E
    HAAG, BL
    MATSUDA, K
    SHICHIRI, M
    KAHN, CR
    [J]. MOLECULAR ENDOCRINOLOGY, 1995, 9 (10) : 1367 - 1379
  • [4] BLOCKADE OF THE TYPE-I SOMATOMEDIN RECEPTOR INHIBITS GROWTH OF HUMAN-BREAST CANCER-CELLS IN ATHYMIC MICE
    ARTEAGA, CL
    KITTEN, LJ
    CORONADO, EB
    JACOBS, S
    KULL, FC
    ALLRED, DC
    OSBORNE, CK
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1989, 84 (05) : 1418 - 1423
  • [5] INSULIN-LIKE GROWTH FACTOR-II OVEREXPRESSION IN MCF-7 CELLS INDUCES PHENOTYPIC CHANGES ASSOCIATED WITH MALIGNANT PROGRESSION
    CULLEN, KJ
    LIPPMAN, ME
    CHOW, D
    HILL, S
    ROSEN, N
    ZWIEBEL, JA
    [J]. MOLECULAR ENDOCRINOLOGY, 1992, 6 (01) : 91 - 100
  • [6] DAKSIS JI, 1994, ONCOGENE, V9, P3635
  • [7] DALY RJ, 1991, CELL GROWTH DIFFER, V2, P457
  • [8] DAMBROSIO C, 1995, CELL GROWTH DIFFER, V6, P557
  • [9] Paradoxical effects of overexpression of the type I insulin-like growth factor (IGF) receptor on the responsiveness of human breast cancer cells to IGFs and estradiol
    Daws, MR
    Westley, BR
    May, FEB
    [J]. ENDOCRINOLOGY, 1996, 137 (04) : 1177 - 1186
  • [10] ESTROGENIC REGULATION OF GROWTH AND POLYPEPTIDE GROWTH-FACTOR SECRETION IN HUMAN-BREAST CARCINOMA
    DICKSON, RB
    LIPPMAN, ME
    [J]. ENDOCRINE REVIEWS, 1987, 8 (01) : 29 - 43