Oncotarget

Priority Research Papers:

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

Kamila A. Marzec, Mike Z. Lin, Janet L. Martin and Robert C. Baxter _

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Oncotarget. 2015; 6:26583-26598. https://doi.org/10.18632/oncotarget.5612

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Abstract

Kamila A. Marzec1, Mike Z. Lin1, Janet L. Martin1 and Robert C. Baxter1

1 Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, NSW, Australia

Correspondence to:

Robert C. Baxter, email:

Keywords: insulin-like growth factor binding protein-3 (IGFBP-3), p53, DNA damage, breast cancer, chemotherapy

Received: July 27, 2015 Accepted: August 26, 2015 Published: September 10, 2015

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.


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