c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations

Celina M. D'Cruz, Edward J. Gunther, Robert B. Boxer, Jennifer L. Hartman, Louis Sintasath, Susan E. Moody, James D. Cox, Seung I. Ha, George K. Belka, Alexander Golant, Robert Cardiff, Lewis A. Chodosh

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Abstract

Although the process of mammary tumorigenesis requires multiple genetic events, it is unclear to what extent carcinogenesis proceeds through preferred secondary pathways following a specific initiating oncogenic event. Similarly, the extent to which established mammary tumors remain dependent on individual mutations for maintenance of the transformed state is unknown. Here we use the tetracycline regulatory system to conditionally express the human c-MYC oncogene in the mammary epithelium of transgenic mice. MYC encodes a transcription factor implicated in multiple human cancers. In particular, amplification and overexpression of c-MYC in human breast cancers is associated with poor prognosis, although the genetic mechanisms by which c-MYC promotes tumor progression are poorly understood1,2. We show that deregulated c-MYC expression in this inducible system results in the formation of invasive mammary adenocarcinomas, many of which fully regress following c-MYC deinduction. Approximately half of these tumors harbor spontaneous activating point mutations in the ras family of proto-oncogenes with a strong preference for Kras2 compared with Hras1. Nearly all tumors lacking activating ras mutations fully regressed following c-MYC deinduction, whereas tumors bearing ras mutations did not, suggesting that secondary mutations in ras contribute to tumor progression. These findings demonstrate that c-MYC-induced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2.

Original languageEnglish (US)
Pages (from-to)235-239
Number of pages5
JournalNature Medicine
Volume7
Issue number2
DOIs
StatePublished - Feb 22 2001

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

D'Cruz, C. M., Gunther, E. J., Boxer, R. B., Hartman, J. L., Sintasath, L., Moody, S. E., Cox, J. D., Ha, S. I., Belka, G. K., Golant, A., Cardiff, R., & Chodosh, L. A. (2001). c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nature Medicine, 7(2), 235-239. https://doi.org/10.1038/84691