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Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation

Abstract

Previous studies reported that the Tumor Susceptibility Gene 101 (TSG101) is upregulated in selected human malignancies, and the expression of exogenous Tsg101 was suggested to transform immortalized fibroblasts in culture. To date, the potential oncogenic properties of Tsg101 have not been examined in vivo owing to the lack of appropriate model systems. In this study, we show that Tsg101 is highly expressed in a subset of invasive human breast cancers. Based on this observation, we generated the first transgenic mouse model with a targeted overexpression of Tsg101 in the developing mammary gland to test whether exogenous Tsg101 is capable of initiating tumorigenesis. Normal functionality of exogenous Tsg101 was tested by rescuing the survival of Tsg101-deficient mammary epithelial cells in conditional knockout mice. The overexpression of Tsg101 resulted in increased phosphorylation of the epidermal growth factor receptor and downstream activation of MAP kinases. Despite an increase in the activation of these signal transducers, the mammary gland of females expressing exogenous Tsg101 developed normally throughout the reproductive cycle. In aging females, the overexpression of Tsg101 seemed to increase the susceptibility of mammary epithelia toward malignant transformation. However, owing to the long latency of tumor formation and the sporadic occurrence of bona fide mammary cancers, we conclude that the Tsg101 protein has only weak oncogenic properties. Instead of cancer initiation, it is therefore likely that Tsg101 plays a more predominant role in the progression of a subset of spontaneously arising breast cancers.

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Acknowledgements

We are grateful to Dr Robert Cardiff (UC Davis) for providing his expertise in pathology and for the histopathological annotation of images from digitized whole-slide-scanned sections of selected tumor specimen. We thank the members of the UNMC Mouse Genome Engineering Core Facility for performing the pronuclear injections. This work was supported by the Public Health Service grant CA93797 from the National Cancer Institute. Additional financial support provided to KUW by the Nebraska Research Initiative was imperative to finance the maintenance of the mice. MJS received a graduate fellowship through the Nebraska IDeA Networks of Biomedical Research Excellence (Grant No. P20 RR16469).

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Correspondence to K-U Wagner.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Oh, K., Stanton, M., West, W. et al. Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation. Oncogene 26, 5950–5959 (2007). https://doi.org/10.1038/sj.onc.1210401

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