Cyclin-Dependent Kinase 4 Expression Is Essential for Neu-Induced Breast Tumorigenesis

Abstract

Previous work has shown that cyclin D1 expression is required for neu-and ras-induced, but not wnt-or c-myc-induced, breast tumorigenesis in mice. Although cyclin D1 binds and activates cyclin-dependent kinase 4 (Cdk4), thereby mediating activation of a program of E2F-dependent gene expression, it has been suggested that the oncogenic activities of cyclin D1 are independent of Cdk4. To determine whether Cdk4 expression is required for breast tumorigenesis in mice, we have generated compound mice ectopically expressing the neu or wnt oncogenes in the mammary glands of wild-type and Cdk4À/À mice. Our results show that Cdk4 expression is required for efficient neu-induced tumorigenesis but is dispensable for wnt-induced breast tumorigenesis. In contrast to results previously observed in the mammary glands of cyclin D1À/À virgin females, our results show defects in mammary gland development in Cdk4À/À virgin females, suggesting differences in compensatory mechanisms in the absence of either subunit of the cyclin D1/Cdk4 complex. These results suggest that drugs targeted to inhibit Cdk4 activities could be developed to specifically treat certain breast tumors as Cdk4 is not essential for viability. (Cancer Res 2005; 65(22): 10174-8)

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

“…With prolonged intervals, hyperplastic lesions eventually develop owing to cyclin E compensation (Bowe et al, 2002). Consistent with the requisite role of cyclin D1, its catalytic partner cdk4 is also required for tumorigenesis in MMTV-neu mice (Reddy et al, 2005). Other lines of evidence also corroborate the hypothesis that HER2 induces transformation through increased cyclin D1/ cdk4 activity.…”

Cell-specific responses to loss of cyclin-dependent kinases

“…In contrast, specific inhibition of cyclin D1 in cancer cell lines resulted in cell-cycle arrest (Zhou et al, 1995;Arber et al, 1997;Kornmann et al, 1998;Sauter et al, 1999;Lee et al, 2000). Moreover, cyclin D1 or Cdk4-null mice are resistant to breast cancers triggered by the ErbB2 oncogene (Yu et al, 2001Reddy et al, 2005;Landis et al, 2006), skin tumor induced by 7,12-dimethylbenz[2]nthracene/12-O-tetradecanoylphorbol-13-acetate treatment (Robles et al, 1998;Rodriguez-Puebla et al, 2002) or c-myc overexpression (Miliani de Marval et al, 2004). These results highlight a major difference between stem cell and cancer cell proliferation.…”

“…However, lack of Cdks and cyclins could confer some resistance to tumors, indicating a difference between tumors and normal tissue. We mentioned that lack of cyclin D1 or Cdk4 confers resistance to breast or skin tumors (Robles et al, 1998;Yu et al, 2001Yu et al, , 2006Rodriguez-Puebla et al, 2002;Reddy et al, 2005;Landis et al, 2006). Moreover, ablation of CKIs leads to multiple tumors, so it is possible to analyse the consequences of the lack of Cdk activity in the context of non-effective checkpoints (e.g., loss of CKIs, p53 or Rb).…”

CDC25A Levels Determine the Balance of Proliferation and Checkpoint Response

“…[45][46][47] In contrast, MMTV-myc induced tumorigenesis can not be inhibited by the loss of either Cyclin D1 or CDK4. 46,47 As CDC25A was previously shown to be a c-myc target gene, 48 it was predicted that CDC25A might play an important role in myc tumor models. Interestingly, we did not notice any significant delay in MMTV-myc induced tumorigenesis upon hemizygous loss of Cdc25A.…”