Function of PEA3 Ets transcription factors in mammary gland development and oncogenesis

被引:57
作者
Kurpios, NA
Sabolic, NA
Shepherd, TG
Fidalgo, GM
Hassell, JA
机构
[1] McMaster Univ, Dept Biochem, MOBIX, Hamilton, ON L8S 4K1, Canada
[2] McMaster Univ, Med Sci Grad Program, Hamilton, ON L8S 4L8, Canada
[3] McMaster Univ, Dept Biol, Hamilton, ON L8S 4L8, Canada
基金
加拿大健康研究院;
关键词
Ets; PEA3; ERM; ER81; Her-2/Neu; stem/progenitor cells; development; breast cancer; knockout and transgenic mice;
D O I
10.1023/A:1025948823955
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The Ets gene families of mice and man currently comprise 27 genes that encode sequence-specific transcription factors. Ets proteins share an T 85 amino acid structurally conserved ETS DNA binding domain. Genetic analyses in model organisms suggest roles for Ets proteins in embryonic development and various adult physiological processes. Chromosomal translocations involving several ETS genes are associated with Ewing's sarcomas and leukemias, whereas the overexpression of some ETS genes is linked with numerous malignancies, including breast cancer. Indeed PEA3, ETS-1, PDEF, and ELF-3 transcripts have all been reported to be elevated in human breast tumors. Some of the ETS genes that are overexpressed in human breast tumors are also overexpressed in mouse models of this disease. Notably, pea3, as well as its close paralogs er81 and erm, which comprise the pea3 subfamily of ets genes, are coordinately overexpressed in mouse mammary tumors. Genetic analyses in mice reveal required roles for one or more of the PEA3 subfamily Ets proteins in the initiation and progression of mouse mammary tumors. The pea3 subfamily genes are normally expressed in the primitive epithelium of mouse mammary buds during embryogenesis, and these three genes are expressed in epithelial progenitor cells during postnatal mammary gland development. Loss-of-function mutations in the mouse pea3 gene results in increased numbers of terminal end buds and an increased fraction of proliferating cells in these structures, suggesting a role for PEA3 in progenitor cell renewal or terminal differentiation. Taken together these observations suggest that the PEA3 subfamily proteins play key regulatory roles in both mammary gland development and oncogenesis.
引用
收藏
页码:177 / 190
页数:14
相关论文
共 84 条
[21]  
DITTMER J, 1998, BIOCHIM BIOPHYS ACTA, V1377, P1
[22]  
Ducret C, 1999, MOL CELL BIOL, V19, P7076
[23]  
Ghadersohi A, 2001, CLIN CANCER RES, V7, P2731
[24]   FUSION OF PDGF RECEPTOR-BETA TO A NOVEL ETS-LIKE GENE, TEL, IN CHRONIC MYELOMONOCYTIC LEUKEMIA WITH T(512) CHROMOSOMAL TRANSLOCATION [J].
GOLUB, TR ;
BARKER, GF ;
LOVETT, M ;
GILLILAND, DG .
CELL, 1994, 77 (02) :307-316
[25]   Autoinhibition as a transcriptional regulatory mechanism [J].
Graves, BJ ;
Cowley, DO ;
Goetz, TL ;
Petersen, JM ;
Jonsen, MD ;
Gillespie, ME .
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY, 1998, 63 :621-629
[26]   Specificity within the ets family of transcription factors [J].
Graves, BJ ;
Petersen, JM .
ADVANCES IN CANCER RESEARCH, VOL 75, 1998, 75 :1-55
[27]   DNA binding by the ETS domain [J].
Graves, BJ ;
Gillespie, ME ;
McIntosh, LP .
NATURE, 1996, 384 (6607) :322-322
[28]   DNA binding by the ETS-domain transcription factor PEA3 is regulated by intramolecular and intermolecular protein protein interactions [J].
Greenall, A ;
Willingham, N ;
Cheung, E ;
Boam, DS ;
Sharrocks, AD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (19) :16207-16215
[29]   Think globally, act locally: the making of a mouse mammary gland [J].
Hennighausen, L ;
Robinson, GW .
GENES & DEVELOPMENT, 1998, 12 (04) :449-455
[30]   Signaling pathways in mammary gland development [J].
Hennighausen, L ;
Robinson, GW .
DEVELOPMENTAL CELL, 2001, 1 (04) :467-475