Reviews & Analysis

Many factors, including genetic and epigenetic alterations, antigenic drive and the microenvironment, are crucial in the initiation and progression of chronic lymphocytic leukaemia (CLL). How will our growing understanding of CLL biology lead to the translation of therapeutic targets and prognostic markers into clinical practice?

Evidence indicates that the disruption of the circadian clock might be directly linked to cancer. As described here, alterations in clock function could lead to aberrant cellular proliferation, DNA damage responses and altered metabolism.

The mucin family of transmembrane and secreted glycoproteins form a barrier that protects the epithelium. Mucins affect epithelial polarity, inflammation, and cell growth and survival signalling; all of these functions could have roles in tumour formation and progression. This Review highlights the functions of mucins in cancer and discusses how these proteins are being targeted therapeutically.

The p53 pathway is deregulated in almost all tumours making it a prime target for new cancer drug development. This Review discusses the new approaches to drug discovery that are currently being used to target the p53 pathway and the progress made with the drugs that have been developed so far.

Transcription-induced DNA supercoiling has dynamic effects on theMYCpromoter element: it converts duplex DNA to non-duplex DNA structures. These non-duplex DNA structures regulate transcription and are amenable to small-molecule targeting. Does this represent another opportunity for the treatment of tumours?

Recent evidence suggests that caspase 2 may have multiple roles in the response to DNA damage, cell cycle regulation and tumour suppression. These findings are unexpected and have important implications for our understanding of tumorigenesis and the treatment of cancer.

Although the nuclear factor of activated T cells (NFAT) transcription factors have been studied predominantly in the immune system, they are expressed in all tissues. This Review discusses the emerging roles of NFATs in cells that comprise the tumour and tumour microenvironment, and how this pathway might be targeted therapeutically.

The E2F transcription factors function in cell cycle control and are intimately regulated by RB. However, some tumours have concurrentRB1inactivation and E2F overexpression. Are there alternative tumour-promoting activities for the E2F family that are independent of cell cycle regulation?

Signal transducer and activator of transcription (STAT) proteins help determine whether immune responses promote or inhibit tumours. Specifically, STAT3 increases tumour cell proliferation, survival and invasion and activates tumour-promoting inflammation, but also suppresses anti-tumour immune responses. STAT3 is therefore a promising target for cancer therapy.

The Polycomb group (PcG) proteins are transcriptional repressors that regulate lineage choices during development and differentiation and are often deregulated in cancer. How might they become deregulated and how does this contribute to tumorigenesis?

The selective pressures for the retention of primordial p53 genes predated the appearance of cancer. Therefore, wild-type tumour suppressive functions were probably co-opted from unrelated primordial activities. Is it possible to deduce what these early functions might have been?

The Rb–E2f and MDM2–p53 pathways are both defective in most human tumours, indicating that these pathways function independently in the control of cell fate. However, extensive crosstalk between these two pathways also exists. How do they coordinately affect tumour biology?

Target response element sequences are a crucial part of the p53 network. This Review describes how functional response elements can be defined and discusses the implications of non-canonical p53 response elements, which greatly expand the universe of p53-regulated genes, on the part that p53 plays as a tumour suppressor.

When p53 was first discovered, it received relatively little attention from cancer researchers. The road leading to p53's rise to fame, and the recognition ofTP53as the most frequently altered gene in human cancer, has been long and winding. This Timeline examines the rich history of this pivotal tumour suppressor.

p53 is an evolutionarily ancient coordinator of metazoan stress responses and its role in tumour suppression is likely to be a relatively recent adaptation. This Review discusses how such evolutionary retooling of this venerable transcription factor entails compromises that restrict its efficacy as a tumour suppressor.

Understanding the activities of p53 in tumour suppression and in other processes has been substantially aided by the use of mouse models. How have these models evolved and what have they taught us about p53 and tumour suppression?

p53 can regulate numerous aspects of metabolic pathways and thereby influence the metabolic alterations exhibited by tumour cells. However, the contribution of p53 is complex and in some cases might promote, rather than inhibit, tumour progression. So, just what is p53 doing?

How important is the DNA damage response in mobilizing the tumour suppression function of p53? This Review considers how supporting and conflicting evidence about the role of DNA damage response signalling in cancer can be reconciled.

The efficacy of endocrine therapies (such as tamoxifen) in breast cancer is limited by intrinsic and acquired therapeutic resistance. What do we know about the genetic lesions and molecular processes that determine endocrine resistance in the clinic, and how can we use this to improve therapy?

The failure of three Phase III randomized trials that assessed the efficacy of anti-idiotype vaccines for the treatment of follicular lymphoma has raised many questions and controversies. In this article, Maurizio Bendandi expresses his thoughts on these findings and argues that new trials are necessary.