Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations.

BRCA1/2 mutation status is of paramount importance to identify families at risk of Hereditary Breast and Ovarian Cancer (HBOC). Most HBOC and BRCA1/2 mutation studies have focused on highly selected sub-populations, and few data are available for large population cohorts. For this reason, as part of a regional cancer prevention strategy in North-Central Italy, we set up a population-based screening programme to identify all resident HBOC families, and to determine their BRCA1/2 mutation status. To date, 44 different BRCA1/2 variants have been identified in 55 HBOC families. Of the seven newly reported mutations, only BRCA1 Q284X is clearly deleterious. The analysis of clinical disease characteristics in relation to age of disease onset and family history showed a difference between BRCA1/2 wild type and mutation carrier families. Interestingly, BRCA1/2 mutations were significantly more common in women who developed breast cancer

Perspectives on mTOR inhibitors for castration-refractory prostate cancer.

The phosphatidylinositol 3'-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway contributes to prostate cancer progression and transition to androgen-independent disease. Furthermore, recent microarray analysis demonstrates that this pathway is often deregulated during prostate cancer progression. Thus, targeting of PI3K/AKT/mTOR may present a promising therapy for castration-refractory prostate cancer (CRPC). In recent years, several interesting strategies have been developed that interfere with distinct components of the PI3K/AKT/mTOR cascade. This article discusses many of the mechanisms involved, specifically in the context of prostate cancer. In addition, we present an overview of preliminary data on the activity of mTOR inhibitors and on the key steps to evaluate which of these compounds are most suitable for the treatment of prostate cancer. Particular emphasis is also placed on the development of novel perspectives to improve the poor prognosis of patients with CRPC.

Stress induction of HSP30, the plasma membrane heat shock protein gene of Saccharomyces cerevisiae, appears not to use known stress-regulated transcription factors.

More than one transcription factor contributes to the Saccharomyces cerevisiae heat shock response. Many genes are induced through the activation of heat shock factor (Hsf1), a protein that is constitutively bound to heat shock promoter elements (HSEs). Other genes are switched on by Msn2/Msn4-dependent activation of a quite separate promoter element (the stress response element, STRE). While Hsf directs gene activation mainly in response to heat stress, STRE-directed transcription is stimulated not only by heat but also by several other stresses, starvation included. HSP30, encoding the plasma membrane heat shock protein, is shown in this study to be activated by several stresses. It is most strongly induced with heat shock, ethanol and weak organic acid exposure. The HSP30 promoter has no good agreement to the HSE consensus and its stress activation is unaffected by a mutation (hsf1-m3) that causes defective heat shock activation of Hsf1-dependent genes. Activation of HSP30 occurs with some, but not all, STRE-inducing stresses and is largely unaffected either by loss of the Msn2/Msn4 transcription factors or with mutation of all STRE-like consensus sequences of the promoter. Stress activation of HSP30 appears therefore to involve as yet unidentified components of the yeast transcriptional apparatus.