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

Dezhong J. Liao, Geraldine Natarajan, Sandra L. Deming, M. Hunter Jamerson, Michael Johnson, Gloria Chepko, Robert B. Dickson

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46 Scopus citations

Abstract

Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGFα enhanced the process. In c-myc transgenic mice, c-myc expression was high in the hyperplastic mammary epithelium and in the majority of tumor areas. 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 and E occurred only in these tumor foci. Overexpression of cyclin D1 also occurred in the hyperplastic epithelium of tgfα-single and tgfα/c-myc-double transgenic mice. In tgfα/c-myc tumors, cells positive for cyclins D1 and E were randomly spread, without showing a reciprocal relationship to c-myc expression. In contrast to c-myc tumors, most tgfα/c-myc tumors showed undetectable levels of retinoblastoma protein (pRB), and the loss 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 mammary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression. TGFα may play its synergistic role, at least in part, by inducing cyclin D1 and facilitating the loss of pRB.

Original languageEnglish (US)
Pages (from-to)1307-1317
Number of pages11
JournalOncogene
Volume19
Issue number10
DOIs
StatePublished - Mar 2 2000

Keywords

  • Cell cycle
  • Cyclins
  • E2F
  • TGFα
  • c-Myc
  • pRB

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    Liao, D. J., Natarajan, G., Deming, S. L., Jamerson, M. H., Johnson, M., Chepko, G., & Dickson, R. B. (2000). Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis. Oncogene, 19(10), 1307-1317. https://doi.org/10.1038/sj.onc.1203430