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HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

Oncogene volume 22, pages 6739–6747 (2003)Cite this article

Abstract

The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR also known as fenretinide) is a potent inducer of apoptosis in breast cancer cells. We observed a 4.5-fold reduction in 4-HPR-mediated apoptosis in MCF-7 breast cancer cells transfected with HER2/neu (MCF-7/HER2) as compared with the parental MCF-7 (MCF-7/WT) cells. Blocking HER2/neu with trastuzumab (HerceptinTM) led to a six-fold increase in 4-HPR-induced apoptosis in HER2/neu-overexpressing cells. These data indicate that HER2/neu reduces the sensitivity of breast cancer cells to 4-HPR. We showed previously that nitric oxide (NO) is essential for 4-HPR to induce apoptosis in breast cancer cells. The inhibitory effects of the 4-HPR and trastuzumab combination correlated with the amount of NO produced in HER2/neu-overexpressing cells. When a NO synthase (NOS) inhibitor was used to block NO production, decreased apoptosis by the 4-HPR and trastuzumab combination was observed. Furthermore, 4-HPR-mediated NOSII expression was lower in MCF-7/HER2 than MCF-7/WT cells, but was increased by trastuzumab in HER2/neu-overexpressing cells. Here we report the novel findings that HER2/neu reduces the ability of 4-HPR to induce apoptosis in breast cancer cells, and that one mechanism by which HER2/neu increases the resistance of breast cancer cells to 4-HPR is by decreasing NOSII-mediated NO production.

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Acknowledgements

This work was supported in part by The Elsa U Pardee Foundation (to AMT) and The King Foundation (to JR). We thank Karen M Ramirez and The University of Texas MD Anderson Cancer Center Department of Immunology Flow Cytometry Core Lab for their technical assistance, and Michael Worley of the Department of Scientific Publications for his editorial review of the manuscript.

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  1. Josh Rosenblum

    Present address: Trinity University, San Antonio, TX, 78212, USA

Authors and Affiliations

  1. Department of Bioimmunotherapy, Section of Immunobiology and Drug Carriers, USA

    Ann-Marie Simeone, Josh Rosenblum & Ana Maria Tari

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lyle David Broemeling

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Correspondence to Ana Maria Tari.

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Simeone, AM., Broemeling, L., Rosenblum, J. et al. HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production. Oncogene 22, 6739–6747 (2003). https://doi.org/10.1038/sj.onc.1206786

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