Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Abstract

Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually. Most tumors and tumor-derived cell lines demonstrated loss of p53 heterozygosity. Furthermore, this tumor susceptibility is related to the number of times the transgene is induced indicating that it is directly attributable to the expression of the cyclin E transgene. An indirect assay indicates that loss of p53 function is an early event occurring in the mammary epithelia of midlactation mammary glands in which cyclin E is deregulated long before evidence of malignancy. These data support the hypothesis that deregulated expression of cyclin E stimulates p53 loss of heterozygosity by promoting genomic instability and provides specific evidence for this in vivo. Cyclin E deregulation and p53 loss are characteristics often observed in human breast carcinoma.

p53 and SCFFbw7 cooperatively restrain cyclin E-associated genome instability

“…For example, Fbw7 heterozygosity was found to accelerate tumorigenesis in p53 heterozygous, but not in p53 null mice, suggesting that the cooperativity resulted primarily from loss of p53 driven by Fbw7-associated genome instability, and that once p53 was mutated, Fbw7 loss was no longer a cooperating event (Mao et al, 2004). Similarly, p53 loss was suggested to be an early consequence of cyclin E transgene expression in a murine breast cancer model, again suggesting that p53 is the critical mutational target of cyclin E-induced instability (Smith et al, 2006). However, while p53-loss is likely to be an important consequence of the genetic instability caused by Fbw7 loss or cyclin E gain, several lines of evidence indicate that p53 function also directly suppresses cyclin E-and Fbw7-associated genetic instability.…”

“…and aberrant cyclin E activity causes genetic instability and tumorigenesis (Spruck et al, 1999;Minella et al, 2002;Loeb et al, 2005;Smith et al, 2006). Many human cancers express high levels of cyclin E (Hwang and Clurman, 2005), and this is thought to directly contribute to cell transformation and tumor aggressiveness.…”

MicroRNA-223 Regulates Cyclin E Activity by Modulating Expression of F-box and WD-40 Domain Protein 7

“…In the absence of a functional Fbw7 pathway, caused either by mutating cyclin E at its CPDs or by deleting FBXW7, cyclin E activity is pathologically sustained throughout the cell cycle, leading to aberrant S-phase progression, delayed mitotic exit, and genome instability (21)(22)(23)(24). In vivo, impaired Fbw7-mediated cyclin E degradation causes increased cell proliferation and impaired maturation in a cell type-specific manner as well as increased tumorigenesis (21,(25)(26)(27). The developmental abnormalities associated with impaired Fbw7-mediated regulation in a cyclin E T74A T393A knock-in mouse model are especially pronounced in erythroid cell precursors, which exhibit hyperproliferation, increased apoptosis, and dysplastic morphologies (25).…”

Both SCFCdc4αand SCFCdc4γare required for cyclin E turnover in cell lines that don’t overexpress cyclin E

“…16,17 Although it has been suggested that excessive levels of cyclin E promote proliferation, the best evidence is that deregulation of cyclin E expression contributes to oncogenesis by causing genomic instability. [18][19][20] One potential mechanism for cyclin E deregulation during oncogenesis is through inactivation of the cyclin E degradation pathway. Indeed, it has been demonstrated that Cdc4 is frequently mutated in a broad spectrum of human cancers, leading to elevated levels and cell cycle deregulation of cyclin E. 9,18,21,22 It is likely therefore that some of the tumorigenic effects of Cdc4 mutation are mediated via cyclin E deregulation.…”