Home LiteratureArticle Details
PMID: 15509777 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Involvement of insulin receptor substrate 2 in mammary tumor metastasis.

Molecular and cellular biology ·Vol. 24 ·No. 22 ·2004-11-00 ·Pages 9726-35

Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM

Abstract

The insulin receptor substrate (IRS) proteins are adaptor molecules that integrate signals generated by receptors that are implicated in human breast cancer. We investigated the specific contribution of IRS-2 to mammary tumor progression using transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and IRS-2-null (IRS-2(-/-)) mice. PyV-MT-induced tumor initiation and growth were similar in wild-type (WT) and IRS-2(-/-) mice. However, the latency and incidence of metastasis were significantly decreased in the absence of IRS-2 expression. The contribution of IRS-2 to metastasis is intrinsic to the tumor cells, because IRS-2(-/-) mammary tumor cells did not metastasize when grown orthotopically in the mammary fat pads of WT mice. WT and IRS-2(-/-) tumors contained similar numbers of mitotic cells, but IRS-2(-/-) tumors had a higher incidence of apoptosis than did WT tumors. In vitro, IRS-2(-/-) mammary tumor cells were less invasive and more apoptotic in response to growth factor deprivation than their WT counterparts. In contrast, IRS-1(-/-) tumor cells, which express only IRS-2, were highly invasive and were resistant to apoptotic stimuli. Collectively, our findings reveal an important contribution of IRS-2 to breast cancer metastasis.

MeSH Terms
Animals Apoptosis Base Sequence Breast Neoplasms/etiology,metabolism Cell Line, Tumor DNA, Neoplasm/genetics Female Humans Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Mammary Neoplasms, Experimental/etiology,genetics,metabolism,secondary Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mitosis Neoplasm Invasiveness Phosphoproteins/deficiency,genetics,metabolism Phosphorylation
Chemicals
DNA, Neoplasm IRS1 protein, human IRS2 protein, human Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Irs1 protein, mouse Irs2 protein, mouse Phosphoproteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Nagle Julie A
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Ma Zhefu
Byrne Maura A
White Morris F
Shaw Leslie M
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.22.9726-9735.2004
Published
2004-11-00
Pages
9726-35
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC525494
Subset
IM
Grants
NCI NIH HHS · R01 CA090583 · United States
NIDDK NIH HHS · R01 DK038712 · United States
NCI NIH HHS · CA90583 · United States
NIDDK NIH HHS · DK38712 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.22.9726-9735.2004 PMC Full Text View journal details
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