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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.
Highlights
Breast cancer is the most common female cancer worldwide [1]
Relative amounts of insulin-like growth factor binding protein-3 (IGFBP-3) mRNA and protein were compared in seven cell lines by plating cells at similar densities and harvesting after 24 h for analysis of IGFBP-3 mRNA by Quantitative real-time PCR (qRT-PCR), and IGFBP-3 protein secreted into media by immunoblotting
Western blot analysis showed that the levels of secreted IGFBP-3 in the conditioned medium, visible www.impactjournals.com/oncotarget as a 35-40 kDa doublet, were highest in the ER-negative breast cancer cell lines compared with the ER-positive lines (Figure 1b)
Summary
Breast cancer is the most common female cancer worldwide [1]. survival rates are high, many women still die from aggressive forms of this disease. IGFBP-3 contributes to cellular apoptosis in both IGF-dependent and -independent manners [6,7,8,9,10,11,12], paradoxically, high IGFBP-3 mRNA and protein levels in breast tumors have been associated with aggressive forms of the disease [13,14,15], perhaps related to its ability to transactivate the EGF receptor [16], promote cell survival by autophagy [17], and contribute to the repair of DNA double-strand breaks [18]. Understanding the regulation of IGFBP-3 expression and actions when p53 is activated, such as during DNA damage, may contribute to a more comprehensive characterization of breast tumors and lead to more effective methods of treatment
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