title: Involvement of p53 in insulin-like growth factor binding protein-3 regulation in the breast cancer cell response to DNA damage.
abstract: Chemotherapy drugs that induce apoptosis by causing DNA double-strand breaks, upregulate the tumor suppressor p53. This study investigated the regulation of the growth-regulatory protein insulin-like growth factor binding protein-3 (IGFBP-3), a p53 target, by DNA-damaging agents in breast cancer cells. IGFBP-3 was upregulated 1.4- to 13-fold in response to doxorubicin and etoposide in MCF-10A, Hs578T, MCF-7 and T47D cells, which express low to moderate basal levels of IGFBP-3. In contrast, IGFBP-3 was strongly downregulated by these agents in cells with high basal levels of IGFBP-3 (MDA-MB-231, MDA-MB-436 and MDA-MB-468). In MDA-MB-468 cells containing the R273H p53 mutation, reported to display gain-of-function properties, chemotherapy-induced suppression of IGFBP-3 was not reversed by the p53 reactivating drug, PRIMA-1, or by p53 silencing, suggesting that the decrease in IGFBP-3 following DNA damage is not a mutant p53 gain-of-function response. SiRNA-mediated downregulation of endogenous IGFBP-3 modestly attenuated doxorubicin-induced apoptosis in MDA-MB-468 and Hs578T cells. IGFBP-3 downregulation in some breast cancer cell lines in response to DNA-damaging chemotherapy may have clinical implications because suppression of IGFBP-3 may modulate the apoptotic response. These observations provide further evidence that endogenous IGFBP-3 plays a role in breast cancer cell responsiveness to DNA damaging therapy.
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia.
authors.forename: Kamila A
authors.initials: KA
authors.lastname: Marzec
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia.
authors.forename: Mike Z
authors.initials: MZ
authors.lastname: Lin
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Martin
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004317:Doxorubicin / Q000737:chemistry; D005047:Etoposide / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C446290:PRIMA1 protein, human; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: DNA damage; breast cancer; chemotherapy; insulin-like growth factor binding protein-3 (IGFBP-3); p53