Involvement of p53 in insulin-like growth factor binding protein-3 regulation in the breast cancer cell response to DNA damage

• Published in: Oncotarget Vol. 6; no. 29; pp. 26583 - 26598
• Main Authors: Marzec, Kamila A, Lin, Mike Z, Martin, Janet L, Baxter, Robert C
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 29.09.2015
• Subjects: Antineoplastic Agents - chemistry; Apoptosis; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Caspase 3 - metabolism; Cell Line, Tumor; DNA Damage; Doxorubicin - chemistry; Etoposide - chemistry; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Membrane Proteins - metabolism; Mutation; Nerve Tissue Proteins - metabolism; Priority Research Paper; Real-Time Polymerase Chain Reaction; RNA, Small Interfering - metabolism; Tumor Suppressor Protein p53 - metabolism; breast cancer; chemotherapy; DNA damage; insulin-like growth factor binding protein-3 (IGFBP-3); p53
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5612

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.