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RISS 인기검색어
- 검색키워드
- 저자 : O'Connor Mark J. (검색결과 3 건)
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Min, Ahrum,Jang, Hyemin,Kim, Seongyeong,Lee, Kyung-Hun,Kim, Debora Keunyoung,Suh, Koung Jin,Yang, Yaewon,Elvin, Paul,O'Connor, Mark J.,Im, Seock-Ah American Association for Cancer Research 2018 Molecular cancer therapeutics Vol.17 No.12
<P>The androgen receptor (AR) is expressed in 60%–70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM–chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation–increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.</P>
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Min, Ahrum,Im, Seock-Ah,Kim, Debora Keunyoung,Song, Sang-Hyun,Kim, Hee-Jun,Lee, Kyung-Hun,Kim, Tae-Yong,Han, Sae-Won,Oh, Do-Youn,Kim, Tae-You,O’Connor, Mark J,Bang, Yung-Jue BioMed Central 2015 Breast cancer research Vol.17 No.-
<P><B>Introduction</B></P><P>Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway.</P><P><B>Methods</B></P><P>We determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These <I>in vitro</I> data were validated <I>in vivo</I> using a human breast cancer xenograft model.</P><P><B>Results</B></P><P>Triple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both <I>in vitro</I> and <I>in vivo</I>.</P><P><B>Conclusion</B></P><P>Our findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13058-015-0534-y) contains supplementary material, which is available to authorized users.</P>
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RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib
Min, Ahrum,Im, Seock-Ah,Yoon, Young-Kwang,Song, Sang-Hyun,Nam, Hyun-Jin,Hur, Hyung-Seok,Kim, Hwang-Phill,Lee, Kyung-Hun,Han, Sae-Won,Oh, Do-Youn,Kim, Tae-You,O'Connor, Mark J.,Kim, Woo-Ho,Bang, Yung-J American Association for Cancer Research 2013 Molecular cancer therapeutics Vol.12 No.6
<P>A PARP inhibitor is a rationally designed targeted therapy for cancers with impaired DNA repair abilities. RAD51C is a paralog of RAD51 that has an important role in the DNA damage response. We found that cell lines sensitive to a novel oral PARP inhibitor, olaparib, had low levels of RAD51C expression using microarray analysis, and we therefore hypothesized that low expression of RAD51C may hamper the DNA repair process, resulting in increased sensitivity to olaparib. Compared with the cells with normal RAD51C expression levels, RAD51C-deficient cancer cells were more sensitive to olaparib, and a higher proportion underwent cell death by inducing G<SUB>2</SUB>–M cell-cycle arrest and apoptosis. The restoration of RAD51C in a sensitive cell line caused attenuation of olaparib sensitivity. In contrast, silencing of RAD51C in a resistant cell line enhanced the sensitivity to olaparib, and the number of RAD51 foci decreased with ablated RAD51C expression. We also found the expression of RAD51C was downregulated in cancer cells due to epigenetic changes and RAD51C expression was low in some gastric cancer tissues. Furthermore, olaparib significantly suppressed RAD51C-deficient tumor growth in a xenograft model. In summary, RAD51C-deficient cancer cells are highly sensitive to olaparib and offer preclinical proof-of-principle that RAD51C deficiency may be considered a biomarker for predicting the antitumor effects of olaparib. <I>Mol Cancer Ther; 12(6); 865–77. ©2013 AACR</I>.</P>
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