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Fgf10 is an oncogene activated by MMTV insertional mutagenesis in mouse mammary tumors and overexpressed in a subset of human breast carcinomas

Abstract

Mouse mammary tumor virus (MMTV) infection causes a high incidence of murine mammary carcinomas by insertion of its proviral DNA in the genome of mammary epithelial cells. Retroviral insertion can activate flanking proto-oncogenes by a process called insertional mutagenesis. By sequencing the DNA adjacent to MMTV proviral insertions in mammary tumors from BALB/c mice infected with C3H-MMTV, we have found a common MMTV insertion site in the Fgf10 locus. RT–PCR studies showed that Fgf10 is expressed only in those tumors harboring a MMTV proviral insertion in this locus, suggesting that Fgf10 is a proto-oncogene. The oncogenicity of Fgf10 was evaluated in vivo by subcutaneous transplantation of retrovirally transduced HC11 mammary epithelial cells into BALB/c mice. Highly vascularized invasive subcutaneous tumors developed indicating that Fgf10 can act as an oncogene. A survey of primary human breast carcinomas revealed strongly elevated Fgf10 mRNA levels in approximately 10% of the tumors tested, suggesting that Fgf10 may also be involved in oncogenicity of a subset of human breast cancers.

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Acknowledgements

We thank Dr L van ’t Veer for the gifts of the human breast carcinoma RNAs. J Collard and R van der Kammen for their retroviral vectors and assistance with the transduction experiments. M Tjin-A-Koeng of the Animal Pathology Department for the immunostaining of the tumor sections. J Hendriksen for helping with the TOP/FOP assays. We thank M Kimm and H de Leeuw for their fruitful discussions and advice and H Pickersgill for reading the manuscript. This work was supported by NKB/KWF Grant 2001-2489.

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Correspondence to John Hilkens.

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Theodorou, V., Boer, M., Weigelt, B. et al. Fgf10 is an oncogene activated by MMTV insertional mutagenesis in mouse mammary tumors and overexpressed in a subset of human breast carcinomas. Oncogene 23, 6047–6055 (2004). https://doi.org/10.1038/sj.onc.1207816

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