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

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 understood. 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.

Reversibility and recurrence of IGF-IR-induced mammary tumors

“…This finding suggests that as tumors increase in size, they acquire additional genetic alterations that allow them to become independent of the initiating oncogene, IGF-IR. Regression rates observed with the 500 mm 3 tumors in the MTB-IGF-IR transgenics were similar to those observed in mammary tumors induced by Wnt1 (Gunther et al, 2003) or constitutively active ErbB2 (Moody et al, 2002) but considerably higher than regression rates observed in c-Myc-induced mammary tumors (D'Cruz et al, 2001;Boxer et al, 2004). The effect of tumor size on regression rates was not explored in these other doxycycline inducible mammary tumor models.…”

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

“…The 1.02 kb constitutively active human Alk5 T204D cDNA fragment including the carboxy-terminal HA tag was subcloned into the pBS-MMTVpA-GSK vector (D'Cruz et al, 2001) (provided by Lewis Chodosh, University of Pennsylvania). The linearized Tg was injected into one-cell-stage FVB mouse embryos, which were transplanted into pseudo-pregnant females.…”

Reconstitution of hTERT restores tumorigenicity in melanoma-derived c-Myc low-expressing clones

“…Overexpression of c-Myc in transgenic mice results in an increased tumor formation, which is greatly enhanced by co-expression of Ras (Sinn et al, 1987). It has recently been demonstrated that c-Myc-induced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2 (D'Cruz et al, 2001). The mechanisms by which c-Myc participates in tumorigenesis are not yet completely understood.…”