title: Involvement of insulin receptor substrate 2 in mammary tumor metastasis.
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.
authors.affiliation: Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Nagle
authors.forename: Zhefu
authors.initials: Z
authors.lastname: Ma
authors.forename: Maura A
authors.initials: MA
authors.lastname: Byrne
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D004273:DNA, Neoplasm; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins