Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development.

Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Research Abstract Details 

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Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Abstract Text:

Dezheng Dong,Min Ni,Jianze Li,Shigang Xiong,Wei Ye,Jenilyn J Virrey,Changhui Mao,Risheng Ye,Miao Wang,Ligaya Pen,Louis Dubeau,Susan Groshen,Florence M Hofman,Amy S Lee,Dezheng Dong,Min Ni,Jianze Li,Shigang Xiong,Wei Ye,Jenilyn J Virrey,Changhui Mao,Risheng Ye,Miao Wang,Ligaya Pen,Louis Dubeau,Susan Groshen,Florence M Hofman,Amy S Lee,

The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity.

Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Publishing Authors By Initials

D Dong,M Ni,J Li,S Xiong,W Ye,JJ Virrey,C Mao,R Ye,M Wang,L Pen,L Dubeau,S Groshen,FM Hofman,AS Lee,D Dong,M Ni,J Li,S Xiong,W Ye,JJ Virrey,C Mao,R Ye,M Wang,L Pen,L Dubeau,S Groshen,FM Hofman,AS Lee,

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Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Cancer research

VOLUME: 68

Page Numbers: 498-505

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 15

MONTH: Jan

YEAR: 2008

Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

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Grant and Affiliation Information for Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development.

AFFILIATION: Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90089-9176, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA 111700

ACRONYM: CA

MEDLINETA: Cancer Res

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