Deregulated cell cycle progression can often be traced to intrinsic defects in specific regulatory proteins in cancer cells. Knowledge of these primary defects has led to targeted approaches that exploit the defects and spare normal cells. However, the success of such targeted approaches is still hit-or-miss. Genetic and epigenetic variability inherent in most tumors often results in phenotypic heterogeneity that, in turn, results in de novo or acquired resistance to therapeutic agents. The ability of cells to compensate and adapt to the inhibition of a specific cell cycle mediator is not remarkable. What is novel and of great potential importance is that the ability of cells to exhibit such adaptability varies markedly. "Phenotypic stability factors" that restrict the ability of cells to undergo epithelial-mesenchymal transitions (EMT) may dictate the success or failure of targeted therapies by interfering with compensatory changes such as deregulation of CDK2 activity. Identification of existing and new agents that induce and maintain phenotypic stability factors will inform and enable synergistic approaches to the eradication of even the most aggressive tumors.

In addition to conferring an indefinite replicative life span, telomerase renders p16(-) human mammary epithelial cells (HMEC) resistant to growth arrest by TGFbeta or by loss of EGF or insulin signaling. In contrast to earlier reports, we recently found that growth factor signaling was not directly affected by telomerase expression. Rather, short dysfunctional or near-dysfunctional telomeres in proliferating telomerase(-) HMEC sensitized the cells to p53-dependent signals for growth arrest. We showed that during serial passage and before any signs of replicative senescence, HMEC lacking telomerase experience enhanced p53 stability and DNA damage signaling, as determined by increased phosphorylation on p53-Ser15 and Chk2-Thr68, and formation of 53BP1/phosphorylated histone H2AX foci at chromosome ends. This heightened activity of the p53 pathway enhanced the efficiency with which cells arrested growth in response to TGFbeta or to EGF or insulin withdrawal, and was abolished by ectopic expression of hTERT, the catalytic subunit of telomerase. Telomerase elongated short telomeres, thereby reducing the basal level of activated p53 and raising cellular tolerance for other p53-dependent signals, including those emanating from non-genotoxic sources. These findings explain a number of observed effects of telomerase expression on cell growth and survival without postulating additional functions for telomerase.

The induction of cellular senescence by activated oncogenes acts as a barrier to cell transformation. Now, identify a key component of a senescence pathway that prevents tumorigenesis in a mouse model of skin cancer. They show that the p38-regulated/activated protein kinase (PRAK) induces senescence downstream of oncogenic Ras by directly phosphorylating and activating the tumor-suppressor protein p53.

Cancer is an age-related disease in organisms with renewable tissues. A malignant tumor arises in part from genomic damage, which can also drive age-related degeneration. However, cancer differs from many age-related degenerative diseases in that it entails gain-of-function changes that confer new (albeit aberrant) properties on cells, resulting in vigorous cell proliferation and survival. Nonetheless, interventions that delay age-related degeneration - for example, caloric restriction or dampened insulin/IGF-1 signaling - often also delay cancer. How then is the development of cancer linked to aging? The answer to this question is complex, as suggested by recent findings. This Hot Topic review discusses some of these findings, including how genomic damage might alter cellular properties without conferring mutations, and how some genes that regulate lifespan in organisms that lack renewable tissues might affect the development of cancer in mammals.

Two recent reports identify ZNF703 as an oncogene driving selection of frequent chromosome 8p12 amplifications in luminal B breast tumors. The estrogen-responsive ZNF703 gene encodes a transcriptional cofactor that, when overexpressed, induces cell proliferation and interferes with transforming growth factor beta signaling. In MCF7 cells, increased ZNF703 expression results in activation of genes involved in stem cell self-renewal - while in primary human mammary epithelial cells, ZNF703 increases the ratio of luminal to basal progenitors. Expression of the murine homolog of ZNF703 reduces cell adhesion and promotes metastasis. ZNF703 overexpression thus alters regulation of proliferation and differentiation in luminal B tumors.

Chromosome 20q13 is highly amplified in human cancers, including 20-30% of early stage human breast cancers. The amplification correlates with poor prognosis. Over-expression of the zinc-finger protein 217 (ZNF217), a candidate oncogene on 20q13.2, in cultured human mammary and ovarian epithelial cells can lead to their immortalization, indicating that selection for ZNF217 expression may drive 20q13 amplification during critical early stages of cancer progression. ZNF217 can also attenuate apoptotic signals resulting from exposure to doxorubicin, suggesting that ZNF217 expression may also be involved in resistance to chemotherapy. Recent findings indicate that ZNF217 binds specific DNA sequences, recruits the co-repressor C-terminal binding protein (CtBP), and represses the transcription of a variety of genes. Inappropriate expression of ZNF217 may lead to aberrant down-regulation of genes involved in limiting the proliferation, survival, and/or invasiveness of cancer cells. Better understanding of ZNF217 and its associated pathways may provide new targets for therapeutic intervention in human cancers.