Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.

The tumour-suppressor phosphatase with tensin homology (PTEN) is the most important negative regulator of the cell-survival signalling pathway initiated by phosphatidylinositol 3-kinase (PI3K). Although PTEN is mutated or deleted in many tumours, deregulation of the PI3K-PTEN network also occurs through other mechanisms. Crosstalk between the PI3K pathways and other tumorigenic signalling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation. How does the PI3K pathway integrate signals from numerous sources, and how can this information be used in the rational design of cancer therapies?

Translational responses to growth factors and stress.

Cellular stresses can induce a wide range of biological responses, depending on the type of stress, the type of cell and the cellular environment. Stress-mediated changes in translational output cover a broad spectrum of potential responses, including an overall decrease in translation or an increase in the translation of specific mRNAs. Many of these changes involve post-translational modifications of components of the translational machinery. The mTOR (mammalian target of rapamycin) pathway is a critical regulator of growth and translation in response to a wide variety of signals, including growth factors, amino acids and energy availability. Through its kinase activity, mTOR activation results in the phosphorylation of translational components and an increase in translation. As stress-mediated changes in translational output are context-dependent, the interplay between stress and mTOR in the control of translation is also likely to depend on factors such as the strength and type of incident stress. In the present paper, we review mTOR-dependent and -independent translational responses, and discuss their regulation by stress.

Transforming acidic coiled coil 1 promotes transformation and mammary tumorigenesis.

Transforming acidic coiled coil 1 (TACC1) is a putative oncogene located within a breast cancer amplicon found on human chromosome 8p11. Although TACC1 has been reported to transform fibroblasts, it is also down-regulated in a subset of mammary tumors treated with anthracyclin. Here, we show that ectopic TACC1 overexpression can cooperate with Ras to induce focus formation in murine fibroblast cultures and prevent death caused by overexpression of Pten or a dominant-negative form of protein kinase B (PKB)/Akt. In transgenic mice carrying TACC1 under the control of the mouse mammary tumor virus promoter, TACC1 expression reduced apoptosis during mammary gland involution, increased the penetrance of mammary tumors in a pten+/- background, and decreased the average age of mammary tumor onset in a mouse model based on a phosphatidylinositol 3'-kinase (PI3K)-decoupled mutant of polyoma middle T. Elevated levels of both phospho-PKB and phospho-extracellular signal-regulated kinase were found in mammary tissue containing the TACC1 transgene. Thus, TACC1 positively regulates the Ras and PI3K pathways, promotes Ras-mediated transformation, and prevents apoptosis induced by PI3K pathway inhibition. TACC1 also cooperates with tumorigenic mutations in the PI3K pathway and thereby plays an oncogenic role in tumor formation in the murine mammary gland.