Review Articles in 2009

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?

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 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.

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.

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?

Recent work has indicated that the p160 SRC family of transcriptional co-activators are subject to amplification and overexpression in various human cancers. This Review discusses the molecular mechanisms responsible, along with the mechanisms by which SRCs promote breast and prostate cancer cell proliferation and survival.

Mutant p53 proteins not only lose their tumour suppressive ability, but also gain new properties that promote tumorigenesis. What are these properties and what are the clinical implications?

In recent years, there has been a tremendous advance in our understanding of the cellular functions of individual RecQ helicases. This Review discusses how these proteins might suppress genomic rearrangements, and therefore function as 'caretaker' tumour suppressors.

The PI3K–Akt pathway is vital to the growth and survival of cancer cells and consequently inhibitors targeting this pathway are entering clinical trials. What is the therapeutic potential of such drugs and what might the challenges and limitations be?

The human tumour suppressor LKB1 directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK is a key therapeutic target in patients with diabetes, and the connection between AMPK and several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants investigation in patients with cancer.