Abstract
Purpose
Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([89Zr]T) binding/uptake.
Procedures
The effect of N-acetylcysteine (NAC) and MUC4 knockdown/stimulation on [89Zr]T binding/uptake were evaluated in MCF7(HER2−), BT474 and SKBr3(HER2+/MUC4−), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and ex vivo analysis.
Results
Significant increases in [89Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4 ± 6.5 %) and exposure to NAC (62.8 ± 19.4 %). Compared to controls, mice treated with NAC showed a significant increase in [89Zr]T uptake in MUC4 tumors on microPET-CT (SUVmean (18.3 ± 4.7 %), SUVmax (41.7 ± 8.4 %)) and individual organ counting (37.3 ± 18.3 %). In contrast, no significant differences were observed in SKBr3.
Conclusion
NAC can enhance [89Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation.
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References
Sergina NV, Moasser MM (2007) The HER family and cancer: emerging molecular mechanisms and therapeutic targets. Trends Mol Med 13:527–534
Bailey TA, Luan H, Clubb RJ et al (2011) Mechanisms of trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance. J Carcinog 10:28
Schechter AL, Stern DF, Vaidyanathan L et al (1984) The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312:513–516
Slamon DJ, Clark GM, Wong SG et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182
Davoli A, Hocevar BA, Brown TL (2010) Progression and treatment of HER2-positive breast cancer. Cancer Chemother Pharmacol 65:611–623
Mitri Z, Constantine T, O’Regan R (2012) The HER2 receptor in breast cancer: pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract 2012:743193
Mukohara T (2011) Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer. Cancer Sci 102:1–8
Pohlmann PR, Mayer IA, Mernaugh R (2009) Resistance to trastuzumab in breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 15:7479–7491
Mukhopadhyay P, Chakraborty S, Ponnusamy MP et al (2011) Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy. Biochim Biophys Acta 1815:224–240
Carraway KL, Price-Schiavi SA, Komatsu M et al (2001) Muc4/sialomucin complex in the mammary gland and breast cancer. J Mammary Gland Biol Neoplasia 6:323–337
Fiszman GL, Jasnis MA (2011) Molecular mechanisms of trastuzumab resistance in HER2 overexpressing breast cancer. Int J Breast Cancer 2011:352182
Price-Schiavi SA, Jepson S, Li P et al (2002) Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. Int J Cancer J Int Cancer 99:783–791
Nagy P, Friedländer E, Tanner M et al (2005) Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res 65:473–482
Dijkers EC, Oude Munnink TH, Kosterink JG et al (2010) Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther 87:586–592
OudeMunnink TH, Korte MA, Nagengast WB et al (2010) (89)Zr-trastuzumab PET visualises HER2 downregulation by the HSP90 inhibitor NVP-AUY922 in a human tumour xenograft. Eur J Cancer 46:678–684
Dijkers ECF, Kosterink JGW, Rademaker AP et al (2009) Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. J Nucl Med Off Publ Soc Nucl Med 50:974–981
Rennstam K, Jönsson G, Tanner M et al (2007) Cytogenetic characterization and gene expression profiling of the trastuzumab-resistant breast cancer cell line JIMT-1. Cancer Genet Cytogenet 172:95–106
Andrianifahanana M, Agrawal A, Singh AP et al (2005) Synergistic induction of the MUC4 mucin gene by interferon-gamma and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways. Oncogene 24:6143–6154
Kunigal S, Ponnusamy MP, Momi N et al (2012) Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades. Mol Cancer 11:24
Choudhury A, Singh RK, Moniaux N et al (2000) Retinoic acid-dependent transforming growth factor-beta 2-mediated induction of MUC4 mucin expression in human pancreatic tumor cells follows retinoic acid receptor-alpha signaling pathway. J Biol Chem 275:33929–33936
Clark J, Clore EL, Zheng K et al (2010) Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice. PLoS One 5:e12333
Marian AJ, Senthil V, Chen SN, Lombardi R (2006) Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation. J Am Coll Cardiol 47:827–834
El Naqa I, Grigsby P, Apte A et al (2009) Exploring feature-based approaches in PET images for predicting cancer treatment outcomes. Pattern Recogn 42:1162–1171
Van Velden FHP, Cheebsumon P, Yaqub M et al (2011) Evaluation of a cumulative SUV-volume histogram method for parameterizing heterogeneous intratumoural FDG uptake in non-small cell lung cancer PET studies. Eur J Nucl Med Mol Imaging 38:1636–1647
Cotgreave IA (1997) N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol San Diego Calif 38:205–227
Schrier BP, Lichtendonk WJ, Witjes JA (2002) The effect of N-acetyl-l-cysteine on the viscosity of ileal neobladder mucus. World J Urol 20:64–67
De Lorenzo C, Tedesco A, Terrazzano G et al (2004) A human, compact, fully functional anti-ErbB2 antibody as a novel antitumour agent. Br J Cancer 91:1200–1204
Lorenzo CD, Cozzolino R, Carpentieri A et al (2005) Biological properties of a human compact anti-ErbB2 antibody. Carcinogenesis 26:1890–1895
Costantini DL, Chan C, Cai Z et al (2007) (111)In-labeled trastuzumab (Herceptin) modified with nuclear localization sequences (NLS): an Auger electron-emitting radiotherapeutic agent for HER2/neu-amplified breast cancer. J Nucl Med Off Publ Soc Nucl Med 48:1357–1368
Acknowledgments
We express our gratitude to Les Amis de Bordet and Fonds Gaston Ithier for the grants obtained to conduct this study. We thank the nuMix team of the Center for Microscopy and Molecular Imaging (CMMI) for their assistance in the animal experiment work.
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The authors declare that they have no conflict of interest.
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S. Goldman, G. Ghanem and P. Flamen contributed equally to this manuscript.
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Wimana, Z., Gebhart, G., Guiot, T. et al. Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [89Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model. Mol Imaging Biol 17, 697–703 (2015). https://doi.org/10.1007/s11307-015-0840-x
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DOI: https://doi.org/10.1007/s11307-015-0840-x