Cell cycle basis for the onset and progression of c-Myc-induced, TGF alpha-enhanced mouse mammary gland carcinogenesis

Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGF al pha enhanced the process. In c-myc transgenic mice, c-myc expression was hi gh in the hyperplastic mammary epithelium and in the majority of tumor area s. However, the tumors displayed focal areas of low expression of c-myc but high rates of proliferation. In contrast to E2F1 and cyclin A2, which were induced and co-localized with c-myc expression, induction of cyclins D1 an d E occurred only in these tumor foci. Overexpression of cyclin D1 also occ urred in the hyperplastic epithelium of tgf alpha-single and tgf alpha/c-my c-double transgenic mice. In tgf alpha/c-myc tumors, cells positive for cyc lins D1 and E were randomly spread, without showing a reciprocal relationsh ip to c-myc expression. In contrast to c-myc tumors, most tgf alpha/c-myc t umors showed undetectable levels of retinoblastoma protein (pRB), and the l oss of PRB occurred in some cases at the mRNA level. These results suggest that E2F1 and cyclin A2 may be induced by c-Myc to mediate the onset of mam mary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression. TGF alpha may play its synergistic role, at l east in part, by inducing cyclin D1 and facilitating the loss of pRB.