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

Although the process of mammary tumorigenesis requires multiple genetic eve nts, it is unclear to what extent carcinogenesis proceeds through preferred secondary pathways following a specific initiating oncogenic event. Simila rly, the extent to which established mammary tumors remain dependent on ind ividual mutations for maintenance of the transformed state is unknown. Here we use the tetracycline regulatory system to conditionally express the hum an 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 asso ciated with poor prognosis, although the genetic mechanisms by which c-MYC promotes tumor progression are poorly understood(1,2). We show that deregul ated c-MYC expression in this inducible system results in the formation of invasive mammary adenocarcinomas, many of which fully regress following c-M YC deinduction. Approximately half of these tumors harbor spontaneous activ ating point mutations in the ros family of proto-oncogenes with a strong pr eference for Kras2 compared with Hras1. Nearly all tumors lacking activatin g 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-indu ced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2.